Benzimidazoles

ABSTRACT

The invention is directed to physiologically active compounds of the general formula (Ix)  
                 
and compositions containing such compounds, and their prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their prodrugs, as well as to novel compounds within the scope of formula (Ix), and to processes for their preparation. Such compounds and compositions have valuable pharmaceutical properties, in particular the ability to inhibit kinases.

This application is entitled to the benefit of earlier filed FrenchApplication No. 0113868 filed Oct. 26, 2001, British Application No.0206893.0 filed Mar. 22, 2002, British Application No. 0206895.5 filedMar. 22, 2002, U.S. Provisional Application No. 60/395,060 filed Jul.11, 2002, and U.S. Provisional Application No. 60/395,151 filed Jul. 11,2002.

This invention is directed to benzimidazoles of formula (Ix), theirpreparation, pharmaceutical compositions containing these compounds, andtheir pharmaceutical use in the treatment of disease states capable ofbeing modulated by the inhibition of the protein kinases. Such proteinkinases belong especially to the following group: EGFR, Fak, FLK-1,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-R, KDR, PDGFR, tie2,VEGFR, ITK and SYK.

Protein kinases are a family of enzymes that participate in thesignalling events which control the activation, growth anddifferentiation of cells in response to extracellular mediators and tochanges in the environment. In general, these kinases fall into severalgroups; those which preferentially catalyse the phosphorylation ofhydroxy groups of serine and/or threonine residues and those whichpreferentially catalyse the phosphorylation of hydroxy groups oftyrosine residues [S. K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages576-596]. Such phosphorylations may greatly modify the function of theproteins; thus, protein kinases play an important role in regulating awide variety of cell processes including, especially, metabolism, cellproliferation, cell differentiation or cell survival. Among the variouscellular functions in which the activity of a kinase protein isinvolved, certain processes represent attractive targets for treatingcertain diseases. As an example, mention may be made especially ofangiogenesis and the control of the cell cycle, in which kinase proteinscan play an essential role. These processes are essential for the growthof solid tumours and also for other diseases.

Angiogenesis or the formation of new blood vessels by sprouting from thepreexisting vasculature is of central importance for embryonicdevelopment and organogenesis. Should the need arise, the vascularsystem has the potential to generate a network of new vessels so as tomaintain the correct functioning of the tissues and organs. Angiogenesisis a complex multistage process which includes activation, migration,proliferation and survival of endothelial cells. In adults, angiogenesisis fairly limited, appearing mainly only in the processes of repairafter an injury or of vascularization of the endometrium. (Merenmies etal., Cell Growth & Differentiation, 8, 3-10, 1997). However,uncontrolled angiogenesis is found in certain pathologies such asretinopathy, psoriasis, rheumatoid arthritis, diabetes, muscledegeneration or cancer (solid tumours) (Folkman, Nature Med., 1, 27-31,1995). The kinase proteins whose involvement it has been possible todemonstrate in the angiogenesis process include three members of thefamily of growth factor receptor tyrosine kinases: VEGF-R2 (vascularendothelial growth factor receptor 2, also known as KDR, kinase insertdomain receptor, or FLK-1), FGF-R (fibroblast growth factor receptor)and TEK (also known as Tie-2).

In conjunction with other systems, the Vascular Endothelial GrowthFactor receptors (VEGFRs) transmit signals involved in the migration,proliferation and survival of endothelial cells. The family VEGFRincludes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4). The receptorVEGF-R2, which is expressed only in the endothelial cells, binds to theangiogenic growth factor VEGF, and thus serves as a transduction signalmediator via the activation of its intracellular kinase domain. Thus,the direct inhibition of the kinase activity of VEGF-R2 makes itpossible to reduce the phenomenon of angiogenesis in the presence ofexogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996),this process being demonstrated especially with the aid of VEGF-R2mutants (Millauer et al., Cancer Research, 56, 1615-1620, 1996). TheVEGF-R2 receptor appears to have no other function in adults than thatassociated with the angiogenic activity of VEGF. Thus, a selectiveinhibitor of the kinase activity of VEGF-R2 should show only littletoxicity.

In addition to this central role in the dynamic angiogenic process,recent results suggest that the expression of VEGF contributes towardsthe survival of tumoral cells after chemotherapy and radiotherapy,underlining the potential synergism of KDR inhibitors with other agents(Lee C. G., Heijn M. et al., (2000), Cancer Research, 60 (19), 5565-70).The KDR inhibitors thus especially constitute anti-angiogenic agents andsuch agents might be used as a first line treatment against theemergence or regrowth of malignant tumours. The inhibition or regulationof VEGFR-2 (KDR) thus provides a powerful new mechanism of action forthe treatment of a large number of solid tumours.

Extensive studies in the field of tumor angiogenesis in the past twodecades have identified a number of therapeutic targets includingkinases, proteases and integrins resulting in the discovery of many newanti-angiogenic agents, including KDR inhibitors some of which arecurrently under clinical evaluation (Jekunen, et al Cancer TreatmentRev. 1997, 23, pages 263-286.).

The present patent application thus relates particularly to novelinhibitors of the VEGFR-2 (KDR) receptor that may be used especially foranti-angiogenic treatment in oncology.

The protein kinases which preferentially catalyse the phosphorylation ofhydroxy groups of serine and/or threonine residues include for example,protein kinase C isoforms [A. C. Newton, J. Biol. Chem., 1995, 270,pages 28495-28498] and a group of cyclin-dependent kinases such as cdk2[J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. Theprotein kinases which preferentially catalyse the phosphorylation ofhydroxy groups of serine and/or threonine residues includemembrane-spanning growth factor receptors such as the epidermal growthfactor receptor [S. Iwashita and M. Kobayashi, Cellular Signalling,1992, 4, pages 123-132], and cytosolic non-receptor kinases such asp56lck, p59fYn, ZAP-70 and csk kinases [C. Chan et. al., Ann. Rev.Immunol., 1994, 12, pages 555-592].

Inappropriately high protein kinase activity has been implicated in manydiseases resulting from abnormal cellular function. This might ariseeither directly or indirectly, for example by failure of the propercontrol mechanisms for the kinase, related for example to mutation,over-expression or inappropriate activation of the enzyme; or by over-or underproduction of cytokines or growth factors also participating inthe transduction of signals upstream or downstream of the kinase. In allof these instances, selective inhibition of the action of the kinasemight be expected to have a beneficial effect.

SYK (Spleen Tyrosine Kinase) is a 72-kDa cytoplasmic protein tyrosinekinase that is expressed in a variety of hematopoietic cells and is anessential element in several cascades that couple antigen receptors tocellular responses. Thus, SYK plays a pivotal role in signalling of thehigh affinity IgE receptor, FcεR1, in mast cells and in receptor antigensignalling in T and B lymphocytes. The signal transduction pathwayspresent in mast, T and B cells have common features. The ligand bindingdomain of the receptor lacks intrinsic tyrosine kinase activity.However, they interact with transducing subunits that containimmunoreceptor tyrosine based activation motifs (ITAMs) [M. Reth,Nature, 1989, 338, pages 383-384]. These motifs are present in both theβ and γ subunits of the FcεR1, in the ξ-subunit of the T cell receptor(TCR) and in the IgGα and IgG β subunits of the B cell receptor (BCR).[N. S. van Oers and A. Weiss, Seminars in Immunology, 1995, 7, pages227-236] Upon binding of antigen and multimerization, the ITAM residuesare phosphorylated by protein tyrosine kinases of the Src family. SYKbelongs to a unique class of tyrosine kinases that have two tandem Srchomology 2 (SH2) domains and a C terminal catalytic domain. These SH2domains bind with high affinity to ITAMs and this SH2-mediatedassociation of SYK with an activated receptor stimulates SYK kinaseactivity and localises SYK to the plasma membrane.

In SYK deficient mice, mast cell degranulation is inhibited, suggestingthat this is an important target for the development of mast cellstabilising agents [P. S. Costello, Oncogene, 1996, 13, pages2595-2605]. Similar studies have demonstrated a critical role for SYK inBCR and TCR signalling [A. M. Cheng, Nature, 1995, 378, pages 303-306,(1995) and D. H. Chu et al., Immunological Reviews, 1998, 165, pages167-180]. SYK also appears to be involved in eosinophil survival inresponse to IL-5 and GM-CSF [S. Yousefi et al., J. Exp. Med., 1996, 183,pages 1407-1414]. Despite the key role of SYK in mast cell, BCR and Tcell signalling, little is known about the mechanism by which SYKtransmits downstream effectors. Two adaptor proteins, BLNK (B cellLinker protein, SLP-65) and SLP-76 have been shown to be substrates ofSYK in B cells and mast cells respectively and have been postulated tointerface SYK with downstream effectors [M. Ishiai et al., Immunity,1999, 10, pages 117-125 and L. R. Hendricks-Taylor et al., J. Biol.Chem, 1997, 272, pages 1363-1367]. In addition SYK appears to play animportant role in the CD40 signalling pathway, which plays an importantrole in B cell proliferation [M. Faris et al., J. Exp. Med., 1994, 179,pages 1923-1931].

SYK is further involved in the activation of platelets stimulated viathe low-affinity IgG receptor (Fc gamma-RIIA) or stimulated by collagen[F. Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471-478].

ITK, is a T cell specific tyrosine kinase of the Tec family that isrequired for normal Th2 function. Asthma is a disease characterised byincreased Th2 cytokine production including IL-4. An inhibitor of ITKshould therefore have an impact on disease progression in asthma throughinhibition of Th2 cytokine production.

We have now found a novel group of benzimidazoles, which have valuablepharmaceutical properties, in particular, the ability to inhibit proteinkinases, more particularly, the ability to inhibit the protein kinaseSYK, the protein kinase KDR, the protein kinase tie2 or the proteinkinase ITK.

Thus, in one aspect, the present invention is directed to pharmaceuticalcompositions comprising compounds of general formula (Ix):—

wherein, for the purposes of (Ix):—

-   X represents C—R² and W, Y and Z, which may be identical or    different, represent CH or CR³; or-   W represents CH, X represents N, Y represents CH or CR³, and Z    represents CH or CR³; or-   W represents N, X represents CH or CR², Y represents CH and CR³, and    Z represents CH or CR³; or-   W represents N, X represents CH or CR², Y represents N, and Z is CH    or CR³; or-   W represents N, X represents CH or CR², Y represents CH or CR³, and    Z represents N; or-   W represents N, X represents N, Y represents CH or CR³, and Z    represents CH or CR³;-   A₅ represents H or alkyl;-   R¹ represents aryl or heteroaryl, each optionally substituted by one    or more groups selected from carboxy, cyano, halo, haloalkyl,    hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴,    —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y²,    —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —OS(O)_(n)R⁴,    —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² and —S(O)_(n)OR⁴;-   R² and R³ are such that:-   R² and R³, which may be identical or different, represent H,    carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴,    —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y²,    —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃,    —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or    —S(O)_(n)OR⁴; or-   R² represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro,    R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴,    —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴,    —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y²    or —S(O)_(n)OR⁴ and R³ represents alkyl, haloalkyl, halogen and OR⁶;    or-   R² and R³ groups on adjacent carbon atoms may form a 5- to    6-membered carbon-based ring containing one or more heteroatoms,    which may be identical or different, chosen from O, N and S, and    which may be optionally substituted by alkyl [examples include those    where R² and R³ form a group selected from —O—CH₂—O—, —O—CH₂—CH₂—O—;    —CH₂—O—CH₂—, —CH₂—N(R¹⁴)—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—C(CH₃)₂—CH₂—,    —CH₂—O—CH₂—CH₂—, —CH₂—N(R¹⁴)—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,    —CH₂—C(CH₃)₂—CH₂—CH₂—, —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—,    —CH═CH—N═CH— or —CH═CH—CH═N, in which R¹⁴ is H or alkyl)];-   R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or    heteroaryl, each optionally substituted with one or more    substituents selected from alkyl, aryl, cycloalkyl, heteroaryl,    heterocycloalkyl, halo, hydroxy, hydroxyalkyl, —C(═O)NY³Y⁴,    —C(═O)OR⁶, —N(R⁶)C(═O)NY¹Y², —NY¹Y², —OR⁵ or alkyl substituted by    —NY³Y⁴;-   R⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,    heteroaryl, heteroarylalkyl, heterocycloalkyl or    heterocycloalkylalkyl;-   R⁶ is chosen from the values of R⁵;-   n is zero or an integer 1 or 2;-   Y¹ and Y² are independently hydrogen, alkenyl, aryl, cycloalkyl,    heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl    optionally substituted by one or more groups selected from cyano,    aryl, heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY³Y⁴, —NY³Y⁴ or —OR⁵,    or the group —NY¹Y² may form a cyclic amine;-   Y³ and Y⁴ are independently hydrogen, alkenyl, alkyl, aryl,    arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group    —NY³Y⁴ may form a cyclic amine; all the alkyl (or alk, which    represents alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl,    arylalkyl, heteroaryl and heteroarylalkyl radicals present in the    above radicals furthermore being optionally substituted with one or    more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl,    alkoxy, acylamino (NH—COalk), —C(═O)OR⁶, —C(═O)R⁶, hydroxyalkyl,    carboxyalkyl, S(O)_(n)-alk S(O)_(n)—NH₂, S(O)_(n)—NH(alk),    S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl,    aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴ and NY³Y⁴ radicals, the latter    radicals containing alkyl, aryl and heteroaryl being themselves    optionally substituted with one or more radicals chosen from halogen    atoms and alkyl radicals, free, salified or esterified carboxyl    radicals and acylamino radicals NH—C(O)R⁵; and their corresponding    N-oxides, and their prodrugs, and their acid bioisosteres; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and their prodrugs, and their acid    bioisosteres; together with one or more pharmaceutically acceptable    carriers or excipients.

In another aspect, the invention concerns the compounds of formula (Ix)as defined above wherein R¹ is a pyrazolyl moiety

in which R⁷ is hydrogen or alkyl, and R⁸ and R⁹ are independentlyselected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro,R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y²,—N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OC(═O)R⁴,—OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y²; or R⁸ and R⁹ together withthe carbon atoms to which they are attached form (i) a 5 to 8 memberedcarbocyclic ring optionally substituted by one or more carbocyclic ringsubstituents; (ii) a phenyl ring optionally substituted by one or morearyl group substituents; (iii) a 5 or 6 membered heteroaromatic ring inwhich one or more of the ring members is/are nitrogen, oxygen or sulfur(examples of such groups include furyl, imidazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl,pyrimidinyl, pyrrolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl andtriazolyl groups) and which is optionally substituted by one or moregroups selected from haloalkyl, hydroxy, halo, cyano, nitro, R⁴,—C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)SO₂R⁴, —NY¹Y² and—OR⁵; or (iv) a 5 or 6 membered heterocyclic ring optionally substitutedby alkyl or oxo, and containing a heteroatom-containing group selectedfrom O, S, SO₂, or NY⁵ (where Y⁵ is hydrogen, R⁴, —C(═O)R⁴, —C(═O)NY¹Y²,—C(═O)OR⁴ or —SO₂R⁴); but excluding the compounds:2-(2H-pyrazol-3-yl)-1H-benzoimidazole;2-(5-methyl-2H-pyrazol-3-yl)-1H-benzoimidazole;5-methyl-6-[2-(2H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one;5-methyl-6-[2-(2H-pyrazol-3-yl)-1H-benzoimidazol-4-yl]4,5-dihydro-2H-pyridazin-3-one;3,5-bis(benzimidazol-2-yl)-1H-pyrazole;5,6-dimethyl-2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole;6-methyl-2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole;5,6-dichloro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole;5-nitro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole;2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole-5-carboxylic acid;2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole;5,6-dimethyl-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole;5-methyl-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole;6-chloro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole;5-chloro-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole;5,6-dichloro-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole;N-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide;3-(1H-benzoimidazol-2-yl)-5-(1H-indazol-4-yl)-1H-indazole,3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxyphenol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]isoquinoline;4-{3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline;4-[3-(4-chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline;4-[2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-phenol;3-[5-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole;3-[5-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole;3-[5-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole;3-(1H-benzoimidazol-2-yl)-5-phenyl-1H-indazole;2-(4-bromo-1-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole;2-(5-tert-butyl-1H-pyrazol-3-yl)-1H-benzoimidazole;3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-phenyl)-1H-indazole;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid;5-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-2-hydroxy-benzoicacid methyl ester;5-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-furan-2-carboxylicacid methyl ester; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid (3-hydroxy-4-methoxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(5-hydroxy-1H-pyrazol-3-yl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(1H-pyrazol-3-yl)-amide;[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(9H-purin-6-yl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid dimethylamide;[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-morpholin-4-yl-methanone;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acidpyrazin-2-ylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid cyclohexylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid (1H-indazol-5-yl)-amide;[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-pyrrolidin-1-yl-methanone;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(1H-indazol-5-yl)-amide;[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-[4-(furan-2-carbonyl)-piperazin-1-yl]-methanone;[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-(4-methyl-piperazin-1-yl)-methanone;1-{4-[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-piperazin-1-yl}-ethanone;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(6-methoxy-pyridin-3-yl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(3-hydroxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acidpyridin-4-ylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(2-hydroxy-ethyl)-methyl-amide;3-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-butyricacid ethyl ester; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid (3-hydroxy-propyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid phenylamide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acidpyridin-3-ylamide;3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-6-pyridin-4-yl-1H-indazole;3-(5-chloro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(5-fluoro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylicacid (4-hydroxy-phenyl)-amide;3-(6-tert-butyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(5,6-difluoro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(3-fluoro-4-hydroxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-2,3-dimethyl-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-2-methyl-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid(4-hydroxy-phenyl)-amide;3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acidcyclopropylamide;2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-sulfonicacid amide;4-[3-(6-dimethylamino-1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol;2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-carboxylicacid methylamide;3-methoxy-4-{3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-6-yl}-phenol;2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;4-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol;3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol;3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-phenol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3,5-dimethyl-phenol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-phenoxy-phenol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-benzene-1,3-diol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol;4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol;N-{3-[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-phenyl}-benzamide;6-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one;5-methyl-6-[2-(1-methyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one;8-(1,5-dimethyl-1H-pyrazol-3-yl)-7H-purine;2-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridine and2-(5-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridine.

In the present specification, the term “compounds of the invention”, andequivalent expressions, are meant to embrace compounds of generalformula (Ix) as hereinbefore described, which expression includes theprodrugs, the pharmaceutically acceptable salts, and the solvates, e.g.hydrates, where the context so permits. Similarly, reference tointermediates, whether or not they themselves are claimed, is meant toembrace their salts, and solvates, where the context so permits. For thesake of clarity, particular instances when the context so permits aresometimes indicated in the text, but these instances are purelyillustrative and it is not intended to exclude other instances when thecontext so permits.

As used above for compounds of formula (Ix), and throughout thedescription of the invention hereinafter, the following terms unlessotherwise indicated, shall be understood to have the followingmeanings:—

“Patient” includes both human and other mammals.

“Acid bioisostere” means a group which has chemical and physicalsimilarities producing broadly similar biological properties to acarboxy group (see Lipinski, Annual Reports in Medicinal Chemistry,1986, 21, p283 “Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993,33, pages 576-579 “Application Of Bioisosterism To New Drug Design”;Zhao, Huaxue Tongbao, 1995, pages 34-38 “Bioisosteric Replacement AndDevelopment Of Lead Compounds In Drug Design”; Graham, Theochem, 1995,343, pages 105-109 “Theoretical Studies Applied To Drug Design:ab initioElectronic Distributions In Bioisosteres”). Examples of suitable acidbioisosteres include: —C(═O)—NHOH, —C(═O)—CH₂OH, —C(═O)—CH₂SH,—C(═O)—NH—CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl,arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl,3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl orheterocyclic phenols such as 3-hydroxyisoxazolyl and3-hydoxy-1-methylpyrazolyl.

“Acyl” denotes a radical R—C(═O)— in which R represents a radical chosenfrom a hydrogen atom, linear or branched alkyl radicals containing notmore than 6 carbon atoms; optionally substituted amino; aryl,heteroaryl, cycloalkyl or heterocycloalkyl radicals, for example phenylor pyrrolidinyl radicals: the term “acyl” thus especially denotes, forexample, formyl radicals and acetyl, propionyl, butanoyl, pentanoyl,hexanoyl, benzoyl and pyrrolidinylcarbonyl radicals.

“Acylamino” denotes —C(═O)—NH₂, —C(O)—NH(alk) and —C(O)—N(alk)(alk)radicals: in these radicals, NH(alk) and N(alk)(alk) have the meaningsgiven hereinafter defined.

“Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain and containing one or moredouble bonds. Preferred alkenyl groups have 2 to about 12 carbon atomsin the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4carbon atoms) in the chain. “Branched,” as used herein and throughoutthe text, means that one or more lower alkyl groups such as methyl,ethyl or propyl are attached to a linear chain; here a linear alkenylchain. “Lower alkenyl” means about 2 to about 4 carbon atoms in thechain, which may be straight or branched. Exemplary alkenyl groupsinclude ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and3,7-dimethyl-octa-2,6-dienyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is asdescribed herein. Exemplary alkoxy groups include difluoromethoxy,methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also the linear orbranched positional isomers thereof.

“Alkoxycarbonyl” means an alkyl-O—CO— group in which the alkyl group isas described herein. Exemplary alkoxycarbonyl groups include methoxy-and ethoxycarbonyl.

“Alkyl” means, unless otherwise specified, an aliphatic hydrocarbongroup which may be straight or branched chain having about 1 to about 15carbon atoms in the chain, optionally substituted by one or more halogenatoms. Particular alkyl groups have from 1 to about 6 carbon atoms.“Lower alkyl” as a group or part of a lower alkoxy, lower alkylthio,lower alkylsulfinyl or lower alkylsulfonyl group means unless otherwisespecified, an aliphatic hydrocarbon group which may be a straight orbranched chain having 1 to about 4 carbon atoms in the chain. Exemplaryalkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl,isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, hexyl, isohexyl, heptyl,octyl, nonyl, decyl and dodecyl, and also the linear or branchedpositional isomers thereof. Exemplary alkyl groups substituted by one ormore halogen atoms include trifluoromethyl, difluoromethyl,trifluoroethyl and difluoroethyl.

“Alkylene” means an aliphatic bivalent radical derived from a straightor branched alkyl group, in which the alkyl group is as describedherein. Exemplary alkylene radicals include methylene, ethylene andtrimethylene.

“Alkylenedioxy” means an —O-alkylene-O— group in which alkylene is asdefined above. Exemplary alkylenedioxy groups include methylenedioxy andethylenedioxy.

“Alkylsulfinyl” means an alkyl-SO— group in which the alkyl group is aspreviously described. Preferred alkylsulfinyl groups are those in whichthe alkyl group is C₁₋₄alkyl.

“Alkylsulfonyl” means an alkyl-SO₂— group in which the alkyl group is aspreviously described. Preferred alkylsulfonyl groups are those in whichthe alkyl group is C₁₋₄alkyl.

“Alkylsulfonylcarbamoyl” means an alkyl-SO₂—NH—C(═O)— group in which thealkyl group is as previously described. Preferred alkylsulfonylcarbamoylgroups are those in which the alkyl group is C₁₋₄alkyl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Exemplary alkylthio groups include methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio,isohexylthio and heptylthio, and also the linear or branched positionalisomers thereof. Preferred alkylthio groups have not more than 4 carbonatoms.

“Alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which group may be a straight or branchedchain having about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have 2 to about 12 carbon atoms in the chain; and morepreferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in thechain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl,i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.

“Aroyl” means an aryl-CO— group in which the aryl group is as describedherein. Exemplary aroyl groups include-benzoyl and 1- and 2-naphthoyl.

“Aroylamino” is an aroyl-NH— group wherein aroyl is as previouslydefined.

“Aryl” as a group or part of a group denotes: (i) an optionallysubstituted monocyclic or multicyclic aromatic carbocyclic moiety ofabout 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) anoptionally substituted partially saturated multicyclic aromaticcarbocyclic moiety in which a monocyclic aromatic carbocyclic moiety anda cycloalkyl or cycloalkenyl group are fused together to form a cyclicstructure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Exceptwhere otherwise defined, aryl groups may be substituted with one or morearyl group substituents, which may be the same or different, where “arylgroup substituent” includes, for example, acyl, acylamino, alkoxy,alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio,aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl,arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl,arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo,heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino,heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl,—C(═O)NY¹Y², —NY¹—C(═O)alkyl, —NY¹SO₂alkyl, —NY¹Y², —SO₂NY¹Y² or alkyl,alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl,heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY¹Y², —NY¹Y² or —OR⁵.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkylmoieties are as previously described. Preferred arylalkyl groups containa C₁₋₄alkyl moiety. Exemplary arylalkyl groups include benzyl,2-phenethyl and naphthlenemethyl.

“Arylalkyloxy” means an arylalkyl-O— group in which the arylalkyl groupis as previously described. Exemplary arylalkyloxy groups includebenzyloxy and 1- or 2-naphthalenemethoxy.

“Arylalkyloxycarbonyl” means an arylalkyl-O—CO— group in which thearylalkyl group is as previously described. An exemplaryarylalkyloxycarbonyl group is benzyloxycarbonyl.

“Arylalkylthio” means an arylalkyl-S— group in which the arylalkyl groupis as previously described. An exemplary arylalkylthio group isbenzylthio.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Exemplary aryloxy groups include phenoxy andnaphthoxy, each optionally substituted.

“Aryloxycarbonyl” means an aryl-O—C(═O)— group in which the aryl groupis as previously described. Exemplary aryloxycarbonyl groups includephenoxycarbonyl and naphthoxycarbonyl.

“Arylsulfinyl” means an aryl-SO— group in which the aryl group is aspreviously described.

“Arylsulfonyl” means an aryl-SO₂— group in which the aryl group is aspreviously described.

“Arylsulfonylcarbamoyl” means an aryl-SO₂—NH—C(═O)— group in which thearyl group is as previously described.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

“Carbocyclic” means a saturated ring system comprising carbon atoms.

“Carbocyclic group substituent” includes, for example, acyl, acylamino,alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl,alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl,arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl,arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo,heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino,heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl,—C(═O)NY¹Y², —NY¹—C(═O)alkyl, —NY¹SO₂alkyl, —NY¹Y², —SO₂NY¹Y² or alkyl,alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl,heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY¹Y², —NY¹Y² or —OR⁵.

“Cyclic amine” means a 3 to 8 membered monocyclic cycloalkyl ring systemwherein one of the ring carbon atoms is replaced by nitrogen and which(i) may also contain a further heteroatom-containing group selected fromO, S, SO₂, or NY⁶ (where Y⁶ is hydrogen, alkyl, aryl, arylalkyl,—C(═O)R⁵, —C(═O)OR⁵, —C(—O)NY¹Y² or —SO₂R⁵); and (ii) may be fused toadditional aryl (e.g. phenyl), heteroaryl (e.g. pyridyl),heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclicring system. Exemplary cyclic amines include pyrrolidine, piperidine,morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline andthe like groups.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and havingabout 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenylrings include cyclopentenyl, cyclohexenyl and cycloheptenyl.

“Cycloalkyl” means a saturated monocyclic or bicyclic ring system ofabout 3 to about 10 carbon atoms, optionally substituted by oxo.Exemplary monocyclic cycloalkyl rings include C₃₋₈cycloalkyl rings suchas cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

“Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyland alkyl moieties are as previously described. Exemplary monocycliccycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl.

“Halo” or “halogen” means fluoro, chloro, bromo, or iodo. Preferred arefluoro, bromo and chloro.

“Haloalkyl” means an alkyl group having about 1 to about 6 carbon atomsin the chain and substituted by one or more halo atoms. Exemplaryhaloalkyl groups include trifluoromethyl.

“Heteroaroyl” means a heteroaryl-C(═O)— group in which the heteroarylgroup is as described herein. Exemplary heteroaryl groups includepyridylcarbonyl.

“Heteroaroylamino” means a heteroaroyl-NH— group in which the heteroarylmoiety is as previously described.

“Heteroaryl” as a group or part of a group denotes: (i) an optionallysubstituted aromatic monocyclic or multicyclic organic moiety of about 5to about 10 ring members in which one or more of the ring members is/areelement(s) other than carbon, for example nitrogen, oxygen or sulfur(examples of such groups include benzoimidazolyl, benzothiazolyl, furyl,imidazolyl, indazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl,isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl,thiazolyl, thienyl and triazolyl groups, optionally substituted by oneor more aryl group substituents as defined above except where otherwisedefined); (ii) an optionally substituted partially saturated multicyclicheterocarbocyclic moiety in which a monocyclic heteroaromatic moiety anda cycloalkyl, cycloalkenyl or heterocycloalkyl group are fused togetherto form a cyclic structure (examples of such groups includetetrahydro-indazole, tetrahydro-pyrazolopyridine,5-oxo-1,4,5,6,7,8,9,9a-octahydro-1,2,4,5a-tetraza-cyclopenta[a]naphthyl,optionally substituted by one or more “aryl group substituents” asdefined above, except where otherwise defined). Optional substituentsinclude one or more “aryl group substituents” as defined above, exceptwhere otherwise defined. When R¹ is heteroaryl this may particularlyrepresent pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, thiazolyl,oxazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, phenyl, pyridinyl,oxodihydropyridinyl, pyrimidinyl, indolyl, indazolyl, thienopyrazolyl,tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl,oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl,tetahydropyridinopyrazolyl, or oxodihydropyridinopyrazolyl.

“Heteroarylalkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl moieties are as previously described. Preferredheteroarylalkyl groups contain a C₁₋₄alkyl moiety. Exemplaryheteroarylalkyl groups include pyridylmethyl.

“Heteroarylalkyloxy” means an heteroarylalkyl-O— group in which theheteroarylalkyl group is as previously described. Exemplaryheteroaryloxy groups include optionally substituted pyridylmethoxy.

“Heteroaryloxy” means an heteroaryl-O— group in which the heteroarylgroup is as previously described. Exemplary heteroaryloxy groups includeoptionally substituted pyridyloxy.

“Heteroarylsulfonylcarbamoyl” means a heteroaryl-SO₂—NH—C(═O)— group inwhich the heteroaryl group is as previously described.

“Heterocycloalkyl” means: (i) a cycloalkyl group of about 3 to 10 ringmembers which contains one or more heteroatoms or heteroatom-containinggroups selected from O, S and NY⁶ and may be optionally substituted byoxo (examples of such groups include hexahydropyran, pyrrolidinyl,piperidinyl, tetrahydropyranyl andoctahydro-pyrido[1,2-c]pyrimidin-1-one); (ii) a partially saturatedmulticyclic heterocarbocyclic moiety in which an aryl (or heteroaryl)ring, each optionally substituted by one or more “aryl groupsubstituents,” and a heterocycloalkyl group are fused together to form acyclic structure (examples of such groups include chromanyl,dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

“Heterocycloalkylalkyl” means a heterocycloalkyl-alkyl-group in whichthe heterocycloalkyl and alkyl moieties are as previously described.

“Hydroxyalkyl” means an alkyl group substituted by one or hydroxygroups.

“NH(alk)” and “N(alk)(alk)” denote an amino radical substituted,respectively, with one or two alkyl radicals, such alkyl radicals beinglinear or branched and chosen from alkyl radicals as defined above,preferably containing not more than 4 carbon atoms.

“Prodrug” means a compound which is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of formula (Ix), includingN-oxides thereof. For example an ester of a compound of formula (Ix)containing a hydroxy group may be convertible by hydrolysis in vivo tothe parent molecule. Alternatively, an ester of a compound of formula(Ix) containing a carboxy group may be convertible by hydrolysis in vivoto the parent molecule.

Suitable esters of compounds of formula (Ix) containing a hydroxy groupare, for example acetates, citrates, lactates, tartrates, malonates,oxalates, salicylates, propionates, succinates, fumarates, maleates,methylene-bis-p-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates andquinates.

Suitable esters of compounds of formula (Ix) containing a carboxy groupare, for example, those described by F. J. Leinweber, Drug Metab. Res.,1987, 18, page 379.

An especially useful class of esters of compounds of formula (Ix)containing a hydroxy group, may be formed from acid moieties selectedfrom those described by Bundgaard et. al., J. Med. Chem., 1989, 32,pages 2503-2507, and include substituted (aminomethyl)-benzoates, forexample dialkylamino-methylbenzoates in which the two alkyl groups maybe joined together and/or interrupted by an oxygen atom or by anoptionally substituted nitrogen atom, e.g. an alkylated nitrogen atom,more especially (morpholino-methyl)benzoates, e.g. 3- or4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates,e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.

Where the compound of the invention of formula (Ix) contains a carboxygroup, or a sufficiently acidic bioisostere, base addition salts may beformed and are simply a more convenient form for use; in practice, useof the salt form inherently amounts to use of the free acid form. Thebases which can be used to prepare the base addition salts includepreferably those which produce, when combined with the free acid,pharmaceutically acceptable salts, that is, salts whose cations arenon-toxic to the patient in pharmaceutical doses of the salts, so thatthe beneficial inhibitory effects inherent in the free base are notvitiated by side effects ascribable to the cations. Pharmaceuticallyacceptable salts, including those derived from alkali and alkaline earthmetal salts, within the scope of the invention include those derivedfrom the following bases: sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine,N-methyl-glucamine, lysine, arginine, ornithine, choline,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and thelike.

Some of the compounds of the present invention of formula (Ix) arebasic, and such compounds are useful in the form of the free base or inthe form of a pharmaceutically acceptable acid addition salt thereof.

Acid addition salts are a more convenient form for use; and in practice,use of the salt form inherently amounts to use of the free base form.The acids which can be used to prepare the acid addition salts includepreferably those which produce, when combined with the free base,pharmaceutically acceptable salts, that is, salts whose anions arenon-toxic to the patient in pharmaceutical doses of the salts, so thatthe beneficial inhibitory effects inherent in the free base are notvitiated by side effects ascribable to the anions. Althoughpharmaceutically acceptable salts of said basic compounds are preferred,all acid addition salts are useful as sources of the free base form evenif the particular salt, per se, is desired only as an intermediateproduct as, for example, when the salt is formed only for purposes ofpurification, and identification, or when it is used as intermediate inpreparing a pharmaceutically acceptable salt by ion exchange procedures.Pharmaceutically acceptable salts within the scope of the inventioninclude those derived from mineral acids and organic acids, and includehydrohalides, e.g. hydrochlorides and hydrobromides, sulfates,phosphates, nitrates, sulfamates, acetates, citrates, lactates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methane-sulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates and quinates.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention of compounds of formula (Ix) are useful forthe purposes of purification of the compounds, for example byexploitation of the solubility differences between the salts and theparent compounds, side products and/or starting materials by techniqueswell known to those skilled in the art.

It will be appreciated that compounds of the present invention offormula (Ix) may contain asymmetric centres. These asymmetric centresmay independently be in either the R or S configuration. It will beapparent to those skilled in the art that certain compounds of theinvention may also exhibit geometrical isomerism. It is to be understoodthat the present invention includes individual geometrical isomers andstereoisomers and mixtures thereof, including racemic mixtures, ofcompounds of formula (Ix) hereinabove. Such isomers can be separatedfrom their mixtures, by the application or adaptation of known methods,for example chromatographic techniques and recrystallisation techniques,or they are separately prepared from the appropriate isomers of theirintermediates. Additionally, tautomers of the compounds of formula (Ix)are possible, and the present invention is intended to include alltautomeric forms of the compounds.

One subject of the present invention is thus the compounds of formula(I):

in which:

-   X represents C—R² and W, Y and Z, which may be identical or    different, represent CH or CR³;-   R¹ represents aryl or heteroaryl chosen from pyrazolyl, triazolyl,    imidazolyl, indolyl, indazolyl, thieno-pyrazolyl,    tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,    dihydrofuropyrazolyl, oxodihydropyridazinyl,    tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl,    tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and    oxodihydropyridinopyrazolyl radicals, all these radicals being    optionally substituted with one or more radicals X¹, X² or X³ chosen    from H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)R⁴, OR⁴, NY¹Y²,    COR⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴,    —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y²,    —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —OC(═O)R⁴ and optionally substituted    thienyl, R² and R³ are such that:-   either R² and R³, which may be identical or different, represent H,    R⁴, halogen, haloalkyl, OH, NO₂, CN, OR⁴, COR⁴,    S(O)_(n)R⁴—C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴,    —N(R⁶)SO₂R, —N(R)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴,    —S(O)_(n)NY¹Y², —OC(═O)NY¹Y² and —OC(═O)R⁴-   or R² represents H, R⁴, halogen, haloalkyl, OH, NO₂, CN, OR⁴,    COR⁴S(O)_(n)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y²,    —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴,    —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y² and —OC(═O)R⁴-   and R³ represents alkyl, haloalkyl, halogen and OR⁶-   or R² and R³ together form a 5- to 6-membered carbon-based ring    containing one or more hetero atoms, which may be identical or    different, chosen from O, N and S,-   R⁴ represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,    cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl,    all these radicals being optionally substituted with one or more    radicals chosen from aryl (optionally substituted), halogen, alkyl,    hydroxyalkyl, OH, OR⁵, C(═O)NY³Y⁴, NY³Y⁴, alk-NY³Y⁴ and C(═O)OR⁶,-   R⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and    heterocycloalkylalkyl.-   Y¹ and Y² are such that: either Y¹ and Y², which may be identical or    different, represent H and optionally substituted alkyl, alkenyl,    cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,    arylalkyl, heteroaryl and heteroarylalkyl,-   or Y¹ and Y² form, together with the nitrogen atom to which they are    attached, a cyclic amino radical,-   Y³ and Y⁴ are such that: either Y³ and Y⁴, which may be identical or    different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl,    cycloalkyl, heteroaryl or heteroarylalkyl or Y³ and Y⁴ form,    together with the nitrogen atom to which they are attached, an    optionally substituted cyclic amino radical,-   A₅ represents H or alkyl,-   R⁶ is chosen from the values of R⁵,-   all the alkyl (or alk, which represents alkyl), alkenyl, cycloalkyl,    heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl    radicals present in the above radicals furthermore being optionally    substituted with one or more radicals chosen from halogen atoms and    hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—COalk), —C(═O)OR⁶,    acyl —C(═O)R⁶, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk,    S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O), —N(alk)₂, CF₃, OCF₃, NO₂,    arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴    and NY³Y⁴ radicals,-   the latter radicals containing alkyl, aryl and heteroaryl being    themselves optionally substituted with one or more radicals chosen    from halogen atoms and alkyl radicals, free, salified or esterified    carboxyl radicals and acylamino radicals NH—C(O)R⁵,-   the phenyl radicals furthermore being optionally substituted with a    dioxole radical,-   n represents an integer from 0 to 2,-   it being understood that when R¹ represents an indazolyl radical-   to give the compounds of formula (F) below:-   with X representing H, R² or R³ as defined above, then W necessarily    represents H or unsubstituted alkyl,-   the said compounds of formula (I) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compoundss of formula(I) as defined above corresponding to the formula (Ia):

in which:

-   Xa represents C—R²a and Wa, Ya and Za, which may be identical or    different, represent CH or CR³a;-   R₁a represents aryl or heteroaryl chosen from pyrazolyl, triazolyl    and indazolyl radicals, all these radicals being optionally    substituted with one or more radicals X¹a, X²a or X³a chosen from H,    halogen, OH, R⁴a, OR⁴a, NY¹aY²a, S(O)_(n)Ra, —C(═O)NY¹aY²a,    —C(═O)OR⁴a, —N(R⁶a)C(═O)R⁴a, —N(R⁶a)SO₂R⁴a, —N(R⁶a)C(═O)NY¹aY²a,    —N(R⁶a)C(═O)OR⁴a, —OC(═O)NY¹aY²a, —OC(═O)R⁴a, —OS(O)_(n)R⁴a and    thienyl optionally substituted with an alkyl radical,-   R²a and R³a are such that:-   either R²a and R³a, which may be identical or different, represent    H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a and —C(═O)OH,    and R³a represents alkyl, halogen and OR⁶a,-   or R²a represents H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a,    —C(═O)OR⁴a and —C(═O)OH, and R³a represents alkyl, halogen and OR⁶a,-   or R²a and R³a together form an —O—CH₂—O— or —O—CH₂—CH₂—O— ring,-   R⁴a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,    cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl,    all these radicals being optionally substituted with one or more    radicals chosen from aryl (optionally substituted), halogen, alkyl,    hydroxyalkyl, OH, OR⁵a, C(═O)NY³aY⁴a, NY³aY⁴a, alk-NY³aY⁴a and    C(═O)OR⁶a,-   R⁵a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and    heterocycloalkylalkyl, all these radicals being optionally    substituted,-   Y¹a and Y²a are such that: either Y¹a and Y²a, which may be    identical or different, represent H, alkyl, alkoxyalkyl,    aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl,    cycloalkyl, aryl and heteroaryl, all these radicals being optionally    substituted, or Y¹a and Y²a form, together with the nitrogen atom to    which they are attached, an optionally substituted cyclic amino    radical,-   Y³a and Y⁴a are such that: either Y³a and Y⁴a, which may be    identical or different, represent hydrogen, alkyl, aryl, arylalkyl,    cycloalkyl, heteroaryl or heteroarylalkyl,-   or Y³a and Y⁴a form, together with the nitrogen atom to which they    are attached, a cyclic amino radical,-   A₅ represents H or alkyl,-   all the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,    arylalkyl, heteroaryl and heteroarylalkyl radicals present in the    above radicals furthermore being optionally substituted with one or    more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl,    alkoxy, acylamino (NH—C(O)R⁶a), —C(═O)OR⁶a, acyl —C(═O)R⁶a,    hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O),    —NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl,    heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³aY⁴a and NY³aY⁴a    radicals,-   the latter radicals containing alkyl, aryl and heteroaryl themselves    being optionally substituted with one or more radicals chosen from    halogen atoms and alkyl radicals, alkoxy radicals, free, salified or    esterified carboxyl radicals and acylamino radicals NH—C(O)R⁶a,-   the phenyl radicals furthermore being optionally substituted with a    dioxole radical,-   R⁶a is chosen from the values of R⁵a,-   n represents an integer from 0 to 2,-   the said compounds of formula (Ia) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compounds of formula(I):

in which:

-   X represents C—R² and W, Y and Z, which may be identical or    different, represent CH or CR³;-   R¹ represents aryl or heteroaryl chosen from pyrazolyl, triazolyl,    imidazolyl, indolyl, indazolyl, thienopyrazolyl,    tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,    dihydrofuropyrazolyl, oxodihydropyridazinyl,    tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl,    tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and    oxodihydro-pyridinopyrazolyl radicals, all these radicals optionally    being substituted with one or more radicals X¹, X² or X³ chosen from    H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)R, OR⁴, NY¹Y², COR⁴,    —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴,    —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y²,    —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —OC(═O)R⁴ and optionally substituted    thienyl,-   R² and R³ are such that:-   either R² and R³, which may be identical or different, represent H,    R⁴, halogen, haloalkyl, OH, NO², CN, OR⁴, COR⁴, S(O)_(n)R⁴,    —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴,    —N(R6)SO2R4, —N(R6)C(═O)NY1Y2, —N(R6)C(═O)OR4, —S(O)nOR4,    —S(O)nNY1Y2, —OC(═O)NY¹Y² and —OC(═O)R⁴-   or R² represents H, R⁴, halogen, haloalkyl, OH, NO₂, CN, OR⁴, COR⁴,    S(O)_(n)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴,    —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴,    S(O)_(n)NY¹Y², —OC(═O)NY¹Y² and —OC(═O)R⁴-   and R³ represents alkyl, haloalkyl, halogen and OR⁶-   or R² and R³ together form a 5- to 6-membered carbon-based ring    containing one or more hetero atoms, which may be identical or    different, chosen from O, N and S,-   R⁴ represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl,    cycloalkylalkyl, heterocycloalkyl, hetero-arylalkyl and arylalkyl,    all these radicals being optionally substituted with one or more    radicals chosen from aryl, OH, OR⁵, C(═O)NY³Y⁴, NY³Y⁴ and C(═O)OR⁶,-   R⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and    heterocycloalkylalkyl.-   R⁶ represents H and C1-C4 alkyl,-   n represents an integer from 0 to 2-   Y¹ and Y² are such that: either Y¹ and Y², which may be identical or    different, represent H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl,    heteroaryl or heteroarylalkyl, all these radicals being optionally    substituted with one or more radicals chosen from hydroxyl,    —C(═O)—NY³Y⁴, —C(═O)OR⁶ and NY³Y⁴, or Y¹ and Y² form, together with    the nitrogen atom to which they are attached, a cyclic amino    radical, Y³ and Y⁴ are such that: either Y³ and Y⁴, which may be    identical or different, represent hydrogen, alkenyl, alkyl, aryl,    arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y³ and Y⁴    form, together with the nitrogen atom to which they are attached, a    cyclic amino radical,-   A₅ represents H or alkyl,-   it being understood that when R¹ represents an indazolyl radical to    give the compounds of formula (F) below:    with X representing H, R² or R³ as defined above, then W necessarily    represents H or unsubstituted alkyl,    the said compounds of formula (F) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral bases.

It is obvious that, according to the ring represented by R¹ and itsnumber of members, R¹ can comprise one, two or three substituentsrepresented by X¹, X² and X³.

One subject of the present invention is thus the compounds of formula(I) as defined above corresponding to the formula (Ia):

in which:

-   Xa represents C—R²a and Wa, Ya and Za, which may be identical or    different, represent CH or CR³a;-   R¹a represents aryl or heteroaryl chosen from pyrazolyl, triazolyl    or indazolyl radicals, all these radicals being optionally    substituted with one or more radicals X¹a, X²a or X³a chosen from H,    halogen, OH, R⁴a, OR⁴a, NY¹aY²a, S(O)_(n)R⁴a, —C(═O)NY¹aY²a,    —C(═O)OR⁴a, —N(R⁶a)C(═O)R⁴a, —N(R⁶a)SO₂R⁴a, —N(R⁶a)C(═O)NY¹aY²a,    —N(R⁶a)C(═O)OR⁴a, —OC(═O)NY¹aY²a and —OC(═O)R⁴a, —OS(O)_(n)R⁴a and    thienyl optionally substituted with an alkyl radical,-   R²a and R³a are such that:-   either R²a and R³a, which may be identical or different, represent    H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a, —C(═O)OH, and    R³a represents alkyl, halogen and OR⁶a,-   or R²a represents H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a,    —C(═O)OR⁴a, —C(═O)OH, and R³a represents alkyl, halogen and OR⁶,-   or R²a and R³a together form an —O—CH₂—O or —O—CH₂—CH₂—O— ring,-   R⁴a represents alkyl, cycloalkyl, aryl, heteroaryl,    heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals    being optionally substituted with one or more radicals chosen from    aryl, OH, OR⁵a, C(═O)NY³aY⁴a, NY³aY⁴a and C(═O)OR⁶a,-   R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,    heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and    heterocycloalkylalkyl,-   R⁶a represents H and C1-C4 alkyl,-   n represents an integer from 0 to 2,-   Y¹a and Y²a are such that: either Y¹a and Y²a, which may be    identical or different, represent H, alkyl, cycloalkyl, aryl and    heteroaryl, all these radicals being optionally substituted with one    or more radicals chosen from hydroxyl, —C(═O)—NY³Y⁴, —C(═O)OR⁶ and    NY³Y⁴, or Y¹a and Y²a form, together with the nitrogen atom to which    they are attached, a cyclic amino radical,-   Y³a and Y⁴a are such that: either Y³a and Y⁴a, which may be    identical or different, represent hydrogen, alkyl, aryl, arylalkyl,    cycloalkyl, heteroaryl or heteroarylalkyl, or Y³a and Y⁴a form,    together with the nitrogen atom to which they are attached, a cyclic    amino radical,-   A₅ represents H or alkyl,-   the said compounds of formula (Ia) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral bases.

One subject of the present invention is thus the compounds of formula(I) as defined above corresponding to the formula (IA):

-   -   in which A represents a saturated heterocyclic radical which is        either a 5- or 6-membered monocyclic radical or a bicyclic        radical that is not more than 10-membered, these members being        such that at least two of them represent a nitrogen atom and the        others, which may be identical or different, represent a carbon        member or a hetero atom member chosen from O, N and S, this        heterocycle A being optionally substituted with one or more        radicals XA¹, XA² or XA³ chosen from the values indicated        hereinabove for the radicals X¹, X² or X³,        A₁, A₂, A₃ and A₄, which may be identical or different, are        chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl,        alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy        radicals, a carboxyl radical which is free, salified, esterified        with an alkyl radical or amidated with a radical NA⁶A⁷ such that        either A⁶ and A⁷, which may be identical or different, are        chosen from a hydrogen atom and optionally substituted alkyl,        alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl        radicals, or A⁶ and A⁷ form, together with the nitrogen atom to        which they are attached, an optionally substituted 5- or        6-membered cyclic radical,    -   it being understood that two consecutive radicals among A₁, A₂,        A₃ and A₄ can form, with the benzimidazole radical to which they        are attached, a 5- to 6-membered carbon-based ring containing        one or more hetero atoms, which may be identical or different,        chosen from O, N and S,        A₅ represents a hydrogen atom or an alkyl radical,        R⁶b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl,        phenylalkyl and cycloalkylalkyl,        all the alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl        and heterocycloalkyl radicals present in the above radicals        being optionally substituted with one or more radicals chosen        from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino,        alkylamino, dialkylamino, phenylamino, phenylalkylamino,        acylamino (NH—COR⁶), —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl,        carboxyalkyl, phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂,        S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl,        itself optionally substituted with one or more halogen atoms,        thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and        C(═O)—N(alk)₂ radicals,        all the above alkyl, alkenyl, alkoxy and alkylthio radicals        being linear or branched and containing not more than 4 carbon        atoms,        all the phenyl radicals of the above radicals furthermore being        optionally substituted with a dioxole radical,        n represents an integer from 0 to 2,        the said compounds of formula (IA) being in any possible        racemic, enantiomeric or diastereoisomeric isomer form, and also        the addition salts with mineral and organic acids or with        mineral and organic bases of the said compounds of formula (IA).

A subject of the present invention is thus the compounds of formula (I)as defined above, corresponding to the formula (IAa):

in which Aa represents a pyrazolyl, triazolyl or indazolyl radical, thisheterocycle Aa being optionally substituted with one or more radicalsXA¹, XA² or XA³ chosen from the values indicated hereinabove for theradicals X¹, X² or X³,

-   -   A₁a, A₂a, A₃a and A₄a, which may be identical or different, are        chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl,        alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a        carboxyl radical which is free, salified, esterified with an        alkyl radical or amidated with a radical NA⁶aA⁷a such that        either A⁶a and A⁷a, which may be identical or different, are        chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl,        cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and        pyridylalkyl radicals, or A6a and A7a form, together with the        nitrogen atom to which they are attached, a pyrrolidinyl,        pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl        radical optionally substituted on the second nitrogen atom with        an alkyl or phenyl radical, which are themselves optionally        substituted,    -   it being understood that two consecutive radicals from among        A₁a, A₂a, A₃a and A₄a may form, with the benzimidazole radical        to which they are attached, an optionally substituted 5- to        6-membered carbon-based ring containing one or two oxygen atoms,    -   A₅a represents a hydrogen atom or an alkyl radical,    -   the phenyl and phenoxy radicals above being optionally        substituted with one or more radicals chosen from halogen atoms        and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl,        alkoxy, amino, alkylamino, dialkylamino, phenylamino,        phenylalkylamino, free, salified or esterified carboxyl, and        dioxole radicals,    -   all the alkyl, alkoxy and alkylthio radicals above being linear        or branched and containing not more than 6 carbon atoms,        the said compounds of formula (IAa) being in any possible        racemic, enantiomeric or diastereoisomeric isomer form, and also        the addition salts with mineral and organic acids or with        mineral and organic bases of the said compounds of formula        (IAa).

The substituents X¹, X² and X³ as defined above are in particular suchthat one represents a hydrogen atom and the other two, which may beidentical or different, are chosen from halogen atoms and OH, R⁴a, OR⁴a,CF₃, OCF₃, NO₂, CN, NY¹aY²a, acylamino (NH—COR⁶b), S(O)_(n)-alk,S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, —C(═O)—NH₂,—C(═O)—NH(alk), C(═O)—N(alk)₂, —C(═O)OR⁴a, —N(R⁶b)C(═O)R⁴a,—N(R⁶b)SO₂R⁴a, —N(R⁶b)C(═O)NY¹aY²a, —N(R⁶b)C(═O)OR⁴a, —OC(═O)NY¹aY²a andthienyl radicals, the thienyl radical being optionally substituted withan alkyl radical,

R⁴a, Y¹a, Y²a and R⁶b having the values defined above and alkrepresenting a linear or branched alkyl radical including not more than6 carbon atoms and optionally substituted as indicated above.

All the alkylthio radicals are such that the sulfur atom is optionallyoxidized to sulfone or sulfoxide with one or two oxygen atoms.

Tables I, II and III described below give examples of compoundsillustrating the present invention, with in particular substituentschosen from the values of X¹, X² and X³ as defined above. TABLE I

with X represents hydrogen, halogen or alkoxy as defined above.

-   radicals; and the aryloxyalkyl radicals represent the phenoxyalkyl    radical; all these radicals being optionally substituted as    indicated hereinabove.

One subject of the present invention is, more particularly, thecompounds of formula (I) as defined above corresponding to the formula(IA):

in which A represents a saturated heterocyclic radical which is either a5- or 6-membered monocyclic radical or a bicyclic radical that is notmore than 10-membered, these members being such that at least two ofthem represent a nitrogen atom and the others, which may be identical ordifferent, represent a carbon member or a hetero atom member chosen fromO, N and S, this heterocycle A optionally being substituted with one ormore radicals XA¹, XA² or XA³ chosen from halogen atoms, alkyl, alkoxyor alkylthio radicals or thienyl radicals optionally substituted with analkyl radical,

-   A₁, A₂, A₃ and A₄, which may be identical or different, are chosen    from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy,    nitro, cyano, phenyl and phenoxy radicals, a carboxyl radical which    is free, salified, esterified with an alkyl radical or amidated with    a radical NA⁶A⁷ such that either A⁶ and A⁷, which may be identical    or different, are chosen from a hydrogen atom and alkyl, phenyl,    phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl    radicals, or A⁶ and A⁷ form, together with the nitrogen atom to    which they are attached, a 5- or 6-membered cyclic radical,-   it being understood that two consecutive radicals among A₁, A₂, A₃    and A₄ can form, with the benzimidazole radical to which they are    attached, a 5- to 6-membered carbon-based ring containing one or    more hetero atoms, which may be identical or different, chosen from    O, N and S,-   A₅ represents a hydrogen atom or an alkyl radical,-   all the phenyl, phenoxy, cycloalkyl and heteroarylalkyl radicals    above being optionally substituted with one or more radicals chosen    from halogen atoms and hydroxyl, cyano, trifluoromethyl,    trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino,    phenylamino, phenylalkylamino, free, salified or esterified    carboxyl, and dioxole radicals,

all the alkyl, alkoxy and alkylthio radicals above being linear orbranched and containing not more than 6 carbon atoms, TABLE II

in which NR′R represents NY¹Y² as defined above. TABLE III

in which X represents hydrogen, alkynyl or NHCOCH₂Ph which is optionallysubstituted.

The subject of the present invention is thus the compounds of formula(I) as defined above in which the substituents of the said compounds offormula (I) have the any of the values indicated as defined hereinaboveand in which the aryl radicals represent the phenyl and naphthylradicals; the heteroaryl radicals represent the furyl, thienyl,benzothienyl, thianthrenyl, pyridyl, pyrazolyl, benzimidazolyl,benzofuran, isobenzofuran and dihydrobenzofuran radicals; the cycloalkylradicals represent a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylradical; the heterocycloalkyl radicals represent the hexahydropyran,piperidyl or morpholino radicals; the heterocycloalkylalkyl radicalsrepresent the hexahydropyranylalkyl, piperidylalkyl and morpholinoalkylradicals; the arylalkyl radicals represent the phenylalkyl,ethylenedioxyphenylalkyl and naphthylalkyl radicals; the heteroarylalkylradicals represent the thienylalkyl, pyridylalkyl, furylalkyl,pyrazolylalkyl, benzothienylalkyl, dihydrobenzofuranylalkyl andbenzimidazolylalkyl radicals; the aryloxy radicals represent the phenoxyand naphthyloxy radicals; the arylalkoxy radicals represent thephenylalkoxy and naphthylalkoxy the said compounds of formula (IA) beingin any possible racemic, enantiomeric or diastereoisomeric isomer form,and also the addition salts with mineral and organic acids or withmineral and organic bases of the said compounds of formula (IA).

A subject of the present invention is also, more particularly, thecompounds of formula (D) as defined above, corresponding to the formula(IAb):

in which Ab represents a pyrazolyl or indazolyl radical optionallysubstituted with one or two radicals chosen from halogen atoms and OH,alkyl, alkynyl, —OR⁶b (including alkoxy), —COR⁶b, —O—COR⁶b,—OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b, phenyl, phenylalkyl, CF₃, OCF₃, NO₂,CN, NY¹bY²b, —NH—C(═O)NY¹bY²b, acylamino (NH—CO—R⁶b), S(O)_(n)-alk,S(O)_(n)—NY¹bY²b, —C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)R⁶b,—NH—S(O)_(n)R⁶b, —NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b, —OC(═O)NY¹bY²b andthienyl radicals, all these radicals being optionally substituted,

-   with NY¹bY²b such that either Y¹b and Y²b, which may be identical or    different, are chosen from hydrogen and optionally substituted    alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy,    phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form,    together with the nitrogen atom to which they are attached, a    piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,    -   A₁b, A₂b, A₃b and A₄b, which may be identical or different, are        chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl,        alkenyl, —OR⁶b (including alkoxy), —CO—R⁶b, —O—COR⁶b,        —OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b, nitro, cyano, furyl, thienyl,        benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy        radicals and a carboxyl radical which is free, salified,        esterified with an alkyl radical or amidated with a radical        NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or        different, are chosen from hydrogen and alkyl, alkoxyalkyl,        phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl,        furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl,        pyridylalkyl, benzothienylalkyl, pyrazolylalkyl,        dihydrobenzofuranylalkyl, hexahydropyranylalkyl,        ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all        these radicals being optionally substituted, or A⁶b and A⁷b        form, together with the nitrogen atom to which they are        attached, a pyrrolidinyl, morpholino or piperazinyl radical, the        piperazinyl radical being optionally substituted on the second        nitrogen atom with an alkyl radical itself optionally        substituted,    -   it being understood that two consecutive radicals among A₁b,        A₂b, A₃b and A₄b can form, with the benzimidazole radical to        which they are attached, an optionally substituted    -   4,5-ethylenedioxybenzimid-azole radical or an optionally        substituted    -   4,5-methylenedioxybenzimidazole radical,    -   A₅b represents a hydrogen atom,-   all the above radicals containing alkyl, alkenyl, phenyl, phenoxy,    furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl    being optionally substituted with one or more radicals chosen from    halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino,    dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b),    —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl,    phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk),    S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally    substituted with one or more halogen atoms, thienyl, phenoxy,    phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)—N(alk)₂ radicals,-   with n representing an integer from 0 to 2,-   and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl,    pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline,    quinolone, dihydroquinolone, —NH-phenyl, phenylalkyl and    cycloalkylalkyl, all these radicals being optionally substituted    with a morpholino, piperidyl or phenyl radical itself optionally    substituted with one or more radicals chosen from halogen atoms and    the cyano, CF₃, OCF₃, alkyl, phenyl-S(O)_(n)-alk-phenyl, alkoxy,    NH₂, NHalk, N(alk)₂, SO₂NH₂, SO₂Nalk or SO₂N(alk)₂ radical,    -   all the alkyl, alkenyl, alkoxy and alkylthio radicals above        being linear or branched and containing not more than 10 carbon        atoms,    -   all the phenyl radicals of the above radicals furthermore being        optionally substituted with a dioxole radical,-   the said compounds of formula (IAb) being in any possible racemic,    enantiomeric or diastereomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IAb).

One subject of the present invention is thus in particular the compoundsof formula (I) as defined above corresponding to the formula (IAb) inwhich Ab represents a pyrazolyl or indazolyl radical optionallysubstituted with one or two radicals chosen from halogen atoms and OH,alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF₃, OCF₃, NO₂, CN,NY¹bY²b, —NH—C(═O)NY¹bY²b, acylamino (NH—CO—R⁶b), S(O)_(n)-alk,S(O)_(n)—NY¹bY²b, —C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)R⁵b,—NH—S(O)_(n)R⁶b, —NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b, —OC(═O)NY¹bY²b andthienyl radicals which are optionally substituted,

-   with NY¹bY²b such that either Y¹b and Y²b, which may be identical or    different, are chosen from hydrogen and optionally substituted    alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy,    phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form,    together with the nitrogen atom to which they are attached, a    piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,    -   A₁b, A₂b, A₃b and A₄b, which may be identical or different, are        chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl,        alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl,        naphthyl, thianthrenyl, phenyl and phenoxy radicals and a        carboxyl radical which is free, salified, esterified with an        alkyl radical or amidated with a radical NA⁶bA⁷b such that        either A⁶b and A⁷b, which may be identical or different, are        chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl,        phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl,        naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl,        benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl,        hexahydropyranylalkyl, ethylenedioxyphenylalkyl and        benzimidazolylalkyl radicals, all these radicals being        optionally substituted, or A⁶b and A⁷b form, together with the        nitrogen atom to which they are attached, a pyrrolidinyl,        morpholino or piperazinyl radical, the piperazinyl radical being        optionally substituted on the second nitrogen atom with an alkyl        radical itself optionally substituted,    -   it being understood that two consecutive radicals among A₁b,        A₂b, A₃b and A₄b can form, with the benzimidazole radical to        which they are attached, an optionally substituted    -   4,5-ethylenedioxybenzimidazole radical or an optionally        substituted    -   4,5-methylenedioxybenzimidazole radical,    -   A₅b represents a hydrogen atom,-   all the above radicals containing alkyl, alkenyl, phenyl, phenoxy,    furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl    being optionally substituted with one or more radicals chosen from    halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino,    dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b),    —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl,    phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk),    S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally    substituted with one or more halogen atoms, thienyl, phenoxy,    phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)N(alk)₂ radicals,-   with n representing an integer from 0 to 2,-   and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl,    phenylalkyl and cycloalkylalkyl,    -   all the alkyl, alkenyl, alkoxy and alkylthio radicals above        being linear or branched and containing not more than 10 carbon        atoms,    -   all the phenyl radicals of the above radicals furthermore being        optionally substituted with a dioxole radical,-   the said compounds of formula (IAb) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compoundsof formula (I) as defined above corresponding to the formula (IAb) inwhich Ab represents a pyrazolyl radical substituted with one or tworadicals such that one is chosen from hydrogen, halogen atoms and alkyl,alkynyl, —COR⁶b, phenyl, phenylalkyl, CF₃, NO₂, CN, NY¹bY²b,—NH—C(═O)NY¹bY²b, NH—CO—R⁶b, S(O)_(n)-alk, S(O)_(n)—NY¹bY²b,—C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)R⁶b, —NH—S(O)_(n)R⁶b,—NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b and thienyl radicals, all theseradicals being optionally substituted,

-   and the other is chosen from OH, —OR⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b,    —O(CH₂)_(n)—CO—R⁶b and —OC(═O)NY¹bY²b radicals, all these radicals    being optionally substituted,-   with NY¹bY²b such that Y¹b and Y²b, which may be identical or    different, are chosen from hydrogen and optionally substituted    alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy,    phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form,    together with the nitrogen atom to which they are attached, a    piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical,    -   A₁b, A₂b, A₃b and A₄b, which may be identical or different, are        such that two of them represent hydrogen and the other two,        which may be identical or different, are chosen from a hydrogen        atom, halogen atoms, hydroxyl, alkyl, alkenyl, —OR⁶b (including        alkoxy), —CO—R⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b,        nitro, cyano, furyl, thienyl, benzothienyl, naphthyl,        thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical        which is free, salified, esterified with an alkyl radical or        amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b,        which may be identical or different, are chosen from hydrogen        and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl,        cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl,        thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl,        pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl,        ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all        these radicals being optionally substituted, or A⁶b and A⁷b        form, together with the nitrogen atom to which they are        attached, a pyrrolidinyl, morpholino or piperazinyl radical, the        piperazinyl radical being optionally substituted on the second        nitrogen atom with an alkyl radical itself optionally        substituted,    -   A₅b represents a hydrogen atom,-   all the above radicals containing alkyl, alkenyl, phenyl, phenoxy,    furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl    being optionally substituted with one or more radicals chosen from    halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino,    dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b),    —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl,    phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O), —NH(alk),    S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally    substituted with one or more halogen atoms, thienyl, phenoxy,    phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)—N(alk)₂ radicals,-   with n representing an integer from 0 to 2,-   and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl,    pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline,    quinolone, dihydroquinolone, —NH-phenyl, phenylalkyl and    cycloalkylalkyl, all these radicals being optionally substituted    with a morpholino, piperidyl or phenyl radical itself optionally    substituted with one or more radicals chosen from halogen atoms and    the cyano, CF₃, OCF₃, alkyl, phenyl-S(O)n-alk-phenyl, alkoxy, NH₂,    NHalk, N(alk)₂, SO₂NH₂, SO₂Nalk or SO₂N(alk)₂ radical,    -   all the alkyl, alkenyl, alkoxy and alkylthio radicals above        being linear or branched and containing not more than 10 carbon        atoms,    -   all the phenyl radicals of the above radicals furthermore being        optionally substituted with a dioxole radical,-   the said compounds of formula (IAb) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IAb).

A subject of the present invention is thus in particular the compoundsof formula (I) as defined above corresponding to the formula (IAb) inwhich Ab represents a pyrazolyl or indazolyl radical optionallysubstituted with one or more radicals chosen from halogen atoms andalkyl, alkoxy and thienyl radicals,

-   -   A₁b, A₂b, A₃b and A₄b, which may be identical or different, are        chosen from a hydrogen atom; halogen atoms; radicals of the        following types: hydroxyl, alkyl, alkenyl optionally substituted        with phenyl itself optionally substituted with one or more        halogen atoms, alkoxy, nitro, cyano, furyl, thienyl optionally        substituted with acyl COalk, benzothienyl, naphthyl,        thianthrenyl, phenyl and phenoxy which are optionally        substituted; and a carboxyl radical which is free, salified,        esterified with an alkyl radical or amidated with a radical        NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or        different, are chosen from hydrogen and radicals of the        following types: alkyl, alkoxyalkyl containing not more than 6        carbon atoms, phenoxyalkyl optionally substituted with acylamino        NH—C(O)alk, phenyl, optionally substituted phenylalkyl,        cycloalkylalkyl, cycloalkyl, furylalkyl optionally substituted        with one or more alkyl radicals, naphthylalkyl, thienylalkyl        optionally substituted with alkyl or thienyl, piperidylalkyl        optionally substituted with a carboxyl radical which is free,        salified or esterified with an alkyl radical, pyridylalkyl        optionally substituted with one or more radicals chosen from        halogen and CF3, benzothienylalkyl, pyrazolylalkyl optionally        substituted with one or more alkyl radicals,        dihydrobenzofuranylalkyl, hexahydropyranylalkyl,        ethylenedioxyphenylalkyl, and benzimidazolylalkyl optionally        substituted with one or more alkyl radicals,    -   or A⁶b and A⁷b form, together with the nitrogen atom to which        they are attached, a pyrrolidinyl, morpholino or piperazinyl        radical, the piperazinyl radical being optionally substituted on        the second nitrogen atom with an alkyl radical,    -   it being understood that two consecutive radicals among A₁b,        A₂b, A₃b and A₄b can form, with the benzimidazole radical to        which they are attached, an optionally substituted    -   4,5-ethylenedioxybenzimidazole radical or an optionally        substituted    -   4,5-methylenedioxybenzimidazole radical,    -   A₅a represents a hydrogen atom,        the phenyl, phenoxy and phenylalkyl radicals above being        optionally substituted with one or more radicals chosen from        halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino,        alkylamino, dialkylamino, phenylamino, phenylalkylamino and        NH—COalk radicals, a carboxyl radical which is free, salified or        esterified with an alkyl radical, and hydroxyalkyl,        carboxyalkyl, phenoxyalkyl, alkylthio, SO₂alk, SO₂NH₂,        SO₂—NH(alk), SO₂—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself        optionally substituted with one or more halogen atoms, thienyl,        phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk), C(═O)—N(alk)₂        and C(O)CH₃ radicals,        all the alkyl or alk, alkenyl, alkoxy and alkylthio radicals        above being linear or branched and containing not more than 4        carbon atoms,        all the phenyl radicals of the above radicals furthermore being        optionally substituted with a dioxole radical,        the said compounds of formula (IAb) being in any possible        racemic, enantiomeric or diastereoisomeric isomer form, and also        the addition salts with mineral and organic acids or with        mineral and organic bases of the said compounds of formula        (IAb).

A subject of the present invention is thus in particular the compoundsof formula (I) as defined above corresponding to the formula (IAb) inwhich Ab, A₁b, A₂b, A₃b, A₄b and A₅b have any of the meanings indicatedhereinabove,

-   -   and when one of A₁b, A₂b, A₃b and A₄b represents a carboxyl        radical amidated with a radical NA⁶bA⁷b, then either one of A⁶b        and A⁷b represents a hydrogen atom or an alkyl radical and the        other of A⁶b and A⁷b is chosen from the values defined for A⁶b        and A⁷b, or A⁶b and A⁷b form, together with the nitrogen atom to        which they are attached, a 5- or 6-membered cyclic radical,    -   the other substituents of the said compounds of formula (I)        having the any of the values indicated hereinabove,        the said compounds of formula (IAb) being in any possible        racemic, enantiomeric or diastereoisomeric isomer form, and also        the addition salts with mineral and organic acids or with        mineral and organic bases of the said compounds of formula        (IAb).

A subject of the present invention is thus in particular the compoundsof formula (I) as defined above in which X, W, Y and Z are such that twoor three of them represent CH and the others are chosen from the valuesof CR² or CR³ and, if appropriate, i.e., when two of them represent CHand CR² and CR³ are adjacent to each other, can form a dioxole radical,

-   R², R³ and the other substituents of the said compounds of    formula (I) having any of the values as defined hereinabove,-   the said compounds of formula (I) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (I).

The present invention thus relates in particular to the compounds offormula (IA) as defined above in which A₁, A₂, A₃ and A₄ are such thattwo or three of them represent a hydrogen atom and the others are chosenfrom the values of A₁, A₂, A₃ and A₄ and, if appropriate, i.e., when twoof them represent a hydrogen atom and the other two are on adjacentcarbons, can form a dioxole radical,

-   the other substituents of the compounds of formula (IA) having any    of the values as defined hereinabove,-   the said compounds of formula (IA) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IA).

A subject of the present invention is also, more particularly, thecompounds of formula (I) as defined above, corresponding to the formula(IAa):

in which Aa represents a pyrazolyl, triazolyl or indazolyl radical, thisheterocycle Aa being optionally substituted with one or more radicalsXA¹, XA² or XA³ chosen from halogen atoms, alkyl, alkoxy or alkylthioradicals and thienyl radicals optionally substituted with an alkylradical,

-   A₁a, A₂a, A₃a and A₄a, which may be identical or different, are    chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy,    nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical    which is free, salified, esterified with an alkyl radical or    amidated with a radical NA⁶aA⁷a such that either A⁶a and A⁷a, which    may be identical or different, are chosen from a hydrogen atom and    alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl,    thienylalkyl and pyridylalkyl radicals, or A⁶a and A⁷a form,    together with the nitrogen atom to which they are attached, a    pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or    piperazinyl radical optionally substituted on the second nitrogen    atom with an alkyl or phenyl radical, which are themselves    optionally substituted,-   it being understood that two consecutive radicals from among A₁a,    A₂a, A₃a and A₄a may form, with the benzimidazole radical to which    they are attached, an optionally substituted 5- to 6-membered    carbon-based ring containing one or two oxygen atoms,-   A5a represents a hydrogen atom or an alkyl radical,-   the phenyl and phenoxy radicals above being optionally substituted    with one or more radicals chosen from halogen atoms and hydroxyl,    cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino,    alkylamino, dialkylamino, phenylamino, phenylalkylamino, free,    salified or esterified carboxyl, and dioxole radicals,-   all the alkyl, alkoxy and alkylthio radicals above being linear or    branched and containing not more than 6 carbon atoms,-   the said compounds of formula (IAa) being in any possible racemic,    enantiomeric or diastereoisomeric isomer form, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IAa).

One subject of the present invention is, more particularly, thecompounds of formula (I) as defined above in which R¹ represents apyrazolyl or indazolyl radical, the other substituents having the valuesindicated above or below.

Among the preferred compounds that are particularly noted are thecompounds of formula (I) in which Aa represents a pyrazolyl or indazolylradical optionally substituted as indicated above and below, A₁a, A₂a,A₃a and A₄a are chosen from the following values:

-   -   A₁a represents hydrogen or carboxyl or forms a ring with        the adjacent member A₂a    -   A₄a represents hydrogen or carboxyl or forms a ring with the        adjacent member A₃a    -   A₂a represents a carboxyl radical that is free, salified,        esterified with an optionally substituted alkyl radical or an        amidated carboxyl as indicated above or below,    -   A₂a and A₃a represent two optionally substituted alkyl radicals,        A₅a represents hydrogen.

One subject of the present invention is, even more particularly, thecompounds of formula (I) as defined above, corresponding to the formula(IAb):

in which Ab represents a pyrazolyl or indazolyl radical optionallysubstituted with one or more radicals chosen from halogen atoms andalkyl, alkoxy and thienyl radicals,

-   A₁b, A₂b, A₃b and A₄b, which may be identical or different, are    chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl and    alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl    radical that is free, salified, esterified with an alkyl radical or    amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which    may be identical or different, are chosen from alkyl, phenyl,    phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or    A⁶b and A⁷b form, together with the nitrogen atom to which they are    attached, a pyrrolidinyl, morpholino or piperazinyl radical    optionally substituted on the second nitrogen atom with an alkyl    radical,-   it being understood that two consecutive radicals from among A₁b,    A₂b, A₃b and A₄b may form, with the benzimidazole radical to which    they are attached, an optionally substituted-   4,5-ethylenedioxybenzimidazole radical or    4,5-methylenedioxybenzimidazole radical,-   A₅b represents a hydrogen atom,-   the phenyl and phenoxy radicals above being optionally substituted    with one or more radicals chosen from halogen atoms and hydroxyl,    cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino,    phenylalkylamino and free, salified or esterified carboxyl radicals,-   all the alkyl, alkoxy and alkylthio radicals above being linear or    branched and containing not more than 4 carbon atoms,-   the said compounds of formula (IAb) being in any possible racemic,    enantiomeric or diastereoisomeric isomer from, and also the addition    salts with mineral and organic acids or with mineral and organic    bases of the said compounds of formula (IAb).

With reference to formula (Ix) above, the following are particular andpreferred groupings:

-   R¹ may particularly represent optionally substituted heteroaryl.    Exemplary optionally substituted heteroaryls include    dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl,    oxodihydropyridazinyl, oxodihydropyridinopyrazolyl,    oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl,    thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl,    tetrahydroindazolyl, tetrahydropyranopyrazolyl,    tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl.    Optional substituents include one or more groups selected from    carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴,    —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y²,    —N(R⁶)C(═O)OR⁴, —N(R⁶SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H,    —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y². R¹ more    preferably represents a heteroaryl moiety    in which R⁷, R⁸ and R⁹ are as hereinbefore defined. It will be    appreciated that compounds of formula (Ix) in which R¹ represents a    heteroaryl moiety    and R⁷ is hydrogen can exist in the tautomeric forms-   W may particularly represent CH when X is CR², Y is CH or CR³ and Z    are CH or CR³.-   W may also particularly represent CH when X is N, Y is CH or CR³ and    Z is CH or CR³.-   W may also particularly represent N when X is CH or CR², Y is CH or    CR³ and Z is CH or CR³.-   W may also particularly represent N when X is CH or CR², Y is CH or    CR³ and Z is N.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein.

A particular group of compounds of the invention are compounds offormula (Ixa):—

in which W, X, Y, Z and R⁷ are as hereinbefore defined for compounds offormula (Ix), and R⁸ and R⁹ are independently selected from hydrogen,carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴,—C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴,—N(R⁶)SO₂R⁴, —NY¹Y², —OR⁴, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and—S(O)₂NY¹Y²; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixa) and theirN-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Yrepresents CH and Z represents CH or C—CH₃ are preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Zrepresents CH and Y represents:

are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents C—CH₃,C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl, Y representsC—CH₃, C—CH₂CH₃, C—OCH₃,

and Z represents CH are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Yrepresents C—CH₃ and Z represents C—CH₃ are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixa) in which R⁷ represents hydrogen arepreferred.

Compounds of formula (Ixa) in which R⁸ represents:

are preferred.

Compounds of formula (Ixa) in which R⁹ represents:

are preferred.

A preferred group of compounds of the invention are compounds of formula(Ixa) in which:—W represents CH; X represents CH; Y represents CH; Zrepresents CH or C—CH₃; R⁷ represents hydrogen; R⁸ represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixa) in which:—W represents CH; X represents CH; Z representsCH; Y represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixa) in which:—W represents CH; X represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixa) in which:—W represents CH; X represents CH; Y representsC—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; R⁸ represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixa) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z representsCH; R⁷ represents hydrogen; R⁸ represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixa) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Zrepresents CH; R⁷ represents hydrogen; R⁸ represents

and their corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixa) and their N-oxides and theirprodrugs, and their acid bioisosteres.

Compounds of formula (Ixa) in which R⁸ is hydrogen or —CH₃ and R⁹ is

are particularly preferred.

Compounds of formula (Ixa) in which R⁹ represents hydrogen and R⁸represents

are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is CH, Y is

and Z is CH are particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C—CH₃ or C—CH₂CH₃, Yis

and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C—OCH₃, Y is CH,C—CH₃, C—CH₂CH₃, C—Cl or C—OCH₃ and Z is CH are alsoparticularly-preferred.

Compounds of formula (Ixa) in which W is CH, X is C—OCH₂CH₃, Y is C—Fand Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ atoms form the group —CH₂—CH₂—CH₂—,and Z represents CH are also particularly preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also particularly preferred.

Compounds of formula (Ixa) in which R⁸ is hydrogen or —CH₃ and R⁹ is

are especially preferred.

Compounds of formula (Ixa) in which W is CH, X is CH, Y is

and Z is CH are especially preferred.

Compounds of formula (Ixa) in which W is CH, X is C—CH₃ or C—CH₂CH₃, Yis C—CH₃ or C—CH₂CH₃, C—Cl or C—F and Z is CH are also especiallypreferred.

Compounds of formula (Ixa) in which W is CH, X is C—OCH₃, Y is C—CH₃,C—CH₂CH₃, C—Cl, C—F or C—OCH₃ and Z is CH are also especially preferred.

Compounds of formula (Ixa) in which W is CH, X is C—OCH₂CH₃, Y is C—Clor C—F and Z is CH are also especially preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also especially preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also especially preferred.

Another particular group of compounds of the invention are compounds offormula (Ix) wherein R¹ is a heteroaryl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form an optionally substituted phenyl ring, i.e. compounds offormula (Ixb):—

in which W, X, Y, Z and R⁷ are as hereinbefore defined for compounds offormula (Ix); R¹⁰ is carboxy, cyano, halo, haloalkyl, hydroxy, nitro,R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y²,—N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H,—OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ or —S(O)₂NY¹Y²; and p iszero, or an integer 1; and their corresponding N-oxides, and theirprodrugs, and their acid bioisosteres; and pharmaceutically acceptablesalts and solvates (e.g. hydrates) of compounds of formula (Ixb) andtheir N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixb) in which W represents CH, X represents CH, Yrepresents CH and Z represents CH or C—CH₃ are preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CH, Zrepresents CH and Y represents:

are also preferred.

Compounds of formula (Ixb) in which W represents CH, X represents

and Z represents CH are also preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CH, Yrepresents C—CH₃ and Z represents C—CH₃ are also preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixb) in which R⁷ represents hydrogen arepreferred.

Compounds of formula (Ixb) in which p is zero or one are preferred.

Compounds of formula (Ixb) in which R¹⁰ represents:

-   -   (i) cyano    -   (ii) halo [e.g. chloro, fluoro];    -   (iii) C₁₋₄alkyl [e.g. methyl,    -   (iv) —OR⁴ [e.g. —OCH₃, —OCH₂CH₃]; or    -   (v) —C(═O)NY¹Y² [e.g. —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂,        —C(═O)—N(CH₃)₂ are preferred.

A preferred group of compounds of the invention are compounds of formula(Ixb) in which:—W represents CH; X represents CH; Y represents CH; Zrepresents CH or C—CH₃; R⁷ represents hydrogen; R¹⁰ represents (i)cyano, (ii) halo [e.g. chloro, fluoro], (iii) C₁₋₄alkyl [e.g. methyl],(iv) —OR⁴ [e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y² [e.g. —C(═O)—NH₂,—C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂]; and their corresponding N-oxides,and their prodrugs, and their acid bioisosteres; and pharmaceuticallyacceptable salts and solvates (e.g. hydrates) of compounds of formula(Ixb) and their N-oxides and their prodrugs, and their acidbioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CH; Z representsCH; Y represents

represents hydrogen; p is zero or one; R¹⁰ represents (i) cyano, (ii)halo [e.g. chloro, fluoro], (iii) C₁₋₄alkyl [e.g. methyl], (iv) —OR⁴[e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y² [e.g. —C(═O)—NH₂,—C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂]; and their corresponding N-oxides,and their prodrugs, and their acid bioisosteres; and pharmaceuticallyacceptable salts and solvates (e.g. hydrates) of compounds of formula(Ixb) and their N-oxides and their prodrugs, and their acidbioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents C—CH₃, C—CH₂CH₃,C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents C—CH₃,C—CH₂CH₃,

Z represents CH; R⁷ represents hydrogen; p is zero or one; R¹⁰represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) C₁₋₄alkyl[e.g. methyl], (iv) —OR⁴ [e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y²[e.g. —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₁₃)₂]; and theircorresponding N-oxides, and their prodrugs, and their acid bioisosteres;and pharmaceutically acceptable salts and solvates (e.g. hydrates) ofcompounds of formula (Ixb) and their N-oxides and their prodrugs, andtheir acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CH; Y representsC—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; p is zero or one; R¹⁰represents (i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) C₁₋₄alkyl[e.g. methyl], (iv) —OR⁴ [e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y²[e.g. —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂]; and theircorresponding N-oxides, and their prodrugs, and their acid bioisosteres;and pharmaceutically acceptable salts and solvates (e.g. hydrates) ofcompounds of formula (Ixb) and their N-oxides and their prodrugs, andtheir acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z representsCH; R⁷ represents hydrogen; p is zero or one; R¹⁰ represents (i) cyano,(ii) halo [e.g. chloro, fluoro], (iii) C1-4alkyl [e.g. methyl], (iv)—OR⁴ [e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y² [e.g. —C(═O)—NH₂,—C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂]; and their corresponding N-oxides,and their prodrugs, and their acid bioisosteres; and pharmaceuticallyacceptable salts and solvates (e.g. hydrates) of compounds of formula(Ixb) and their N-oxides and their prodrugs, and their acidbioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Zrepresents CH; R⁷ represents hydrogen; p is zero or one; R¹⁰ represents(i) cyano, (ii) halo [e.g. chloro, fluoro], (iii) C₁₋₄alkyl [e.g.methyl], (iv) —OR⁴ [e.g. —OCH₃ or —OCH₂CH₃] or (v) —C(═O)NY¹Y² [e.g.—C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂]; and theircorresponding N-oxides, and their prodrugs, and their acid bioisosteres;and pharmaceutically acceptable salts and solvates (e.g. hydrates) ofcompounds of formula (Ixb) and their N-oxides and their prodrugs, andtheir acid bioisosteres.

Compounds of formula (Ixb) in which R⁷ represents hydrogen and p is zeroare particularly preferred.

Compounds of formula (Ixb) in which R⁷ represents hydrogen; p is one andR¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃,—C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂ are also particularlypreferred.

Compounds of formula (Ixb) in which W is CH, X is

and Z is CH are particularly preferred.

Compounds of formula (Ixb) in which W is CH, X is

and Z is CH are also particularly preferred.

Compounds of formula (Ixb) in which W is CH, X is C—OCH₃, Y is CH,C—CH₃, C—CH₂CH₃, C—Cl or C—OCH₃ and Z is CH are also particularlypreferred.

Compounds of formula (Ixb) in which W is CH, X is C—OCH₂CH₃, Y is C—Fand Z is CH are also particularly preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also particularly preferred.

Compounds of formula (Ixb) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also particularly preferred.

Compounds of formula (Ixb) in which R⁷ represents hydrogen and p is zeroare especially preferred.

Compounds of formula (Ixb) in which R⁷ represents hydrogen; p is one andR¹⁰ represents —OCH₃, —OCH₂CH₃ or —C(═O)—NHCH(CH₃)₂ attached to position5 of the indazolyl ring are also especially preferred.

Compounds of formula (Ixb) in which W is CH, X is C—CH₃ or C—CH₂CH₃, Yis C—CH₃ or C—CH₂CH₃ and Z is CH are also especially preferred.

Another particular group of compounds of the invention are compounds offormula (Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form an optionally substituted C₅₋₈cycloalkyl ring, i.e.compounds of formula (Ixc):—

in which W, X, Y, Z, X and p are as hereinbefore defined for compoundsof formula (Ix),

is a C₅₋₈cycloalkyl ring and R¹² is acyl, acylamino, alkoxy,alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio,aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl,arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl,arylthio, carboxy (or an acid bioisostere), cyano, cycloalkyl, halo,heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino,heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl,—C(═O)NY¹Y², —NY¹—C(═O)alkyl, —NY¹SO₂alkyl, —NY¹Y², —SO₂NY¹Y² or alkyl,alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl,heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY¹Y², —NY¹Y² or —OR⁵; and theircorresponding N-oxides, and their prodrugs, and their acid bioisosteres;and pharmaceutically acceptable salts and solvates (e.g. hydrates) ofcompounds of formula (Ixc) and their N-oxides and their prodrugs, andtheir acid bioisosteres.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Yrepresents CH and Z represents CH or C—CH₃ are preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Zrepresents CH and Y represents:

are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents C—CH₃,C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl, Y represents

and Z represents CH are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CH, Yrepresents C—CH₃ and Z represents C—CH₃ are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixc) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixc) in which R⁷ represents hydrogen arepreferred.

Compounds of formula (Ixc) in which

represents a cyclopentyl, cyclohexyl and cycloheptyl, especiallycyclohexyl, ring are preferred.

Compounds of formula (Ixc) in which q is zero are preferred.

A preferred group of compounds of the invention are compounds of formula(Ixc) in which:—W represents CH; X represents CH; Y represents CH; Zrepresents CH or C—CH₃; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixc) in which:—W represents CH; X represents CH; Z representsCH; Y represents

R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixc) in which:—W represents CH; X represents C—CH₃, C—CH₂CH₃,C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixc) in which:—W represents CH; X represents CH; Y representsC—CH₃; Z represents C—CH₃; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z representsCH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixb) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Zrepresents CH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; andtheir corresponding N-oxides, and their prodrugs, and their acidbioisosteres; and pharmaceutically acceptable salts and solvates (e.g.hydrates) of compounds of formula (Ixc) and their N-oxides and theirprodrugs, and their acid bioisosteres.

Compounds of formula (Ixc) in which R⁷ represents hydrogen and p is zeroare particularly preferred.

Compounds of formula (Ixc) in which W is CH, X is C—CH₃, Y is C—CH₃ andZ is CH are also particularly preferred.

Compounds of formula (Ixc) in which

is a cyclopentyl ring are particularly preferred.

Another particular group of compounds of the invention are compounds offormula (Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form an optionally substituted heterocycloalkyl ring, i.e.compounds of formula (Ixd):—

in which W, X, Y, Z and X are as hereinbefore defined for compounds offormula (Ix), X¹ is O, S, SO₂, or NY⁵ (where Y⁵ is hydrogen, R⁴,—C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴), r is zero or an integer oneor two and R¹³ is alkyl or two R¹³ groups attached to the same carbonatom form an oxo group; and their corresponding N-oxides, and theirprodrugs, and their acid bioisosteres; and pharmaceutically acceptablesalts and solvates (e.g. hydrates) of compounds of formula (Ixd) andtheir N-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixd) in which W represents CH, X represents CH, Yrepresents CH and Z represents CH or C—CH₃ are preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CH, Zrepresents CH and Y represents:

are also preferred.

Compounds of formula (Ixd) in which W represents CH, X represents C—CH₃,C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl, Y represents

and Z represents CH are also preferred.

Compounds of formula (Ixa) in which W represents CH, X represents CH, Yrepresents C—CH₃ and Z represents C—CH₃ are also preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also preferred.

Compounds of formula (Ixd) in which R⁷ represents hydrogen arepreferred.

Compounds of formula (Ixd) in which X¹ is:

are preferred.

Compounds of formula (Ixd) in which r is zero are preferred.

A preferred group of compounds of the invention are compounds of formula(Ixd) in which:—W represents CH; X represents CH; Y represents CH; Zrepresents CH or C—CH₃; R⁷ represents hydrogen; X¹ is

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixd) in which:—W represents CH; X represents CH; Z representsCH; Y represents

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixd) in which:—W represents CH; X represents C—CH₃, C—CH₂CH₃,C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen; X¹ is

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixd) in which:—W represents CH; X represents CH; Y representsC—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; X¹ is

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixd) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z representsCH; R⁷ represents hydrogen; X¹ is

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

A further preferred group of compounds of the invention are compounds offormula (Ixd) in which:—W represents CH; X represents CR² and Yrepresents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Zrepresents CH; R⁷ represents hydrogen; X¹ is

and r is zero; and their corresponding N-oxides, and their prodrugs, andtheir acid bioisosteres; and pharmaceutically acceptable salts andsolvates (e.g. hydrates) of compounds of formula (Ixd) and theirN-oxides and their prodrugs, and their acid bioisosteres.

Compounds of formula (Ixd) in which X¹ is

N—C(═O)OCH₃ or N—C(═O)OCH₂CH₃ and r is zero are particularly preferred.

Compounds of formula (Ixd) in which W is CH, X is CH, Y is

and Z is CH are particularly preferred.

Compounds of formula (Ixd) in which W is CH, X is C—CH₃ or C—CH₂CH₃, Yis

and Z is CH are also particularly preferred.

Compounds of formula (Ixa) in which W is CH, X is C—OCH₃, Y is CH,C—CH₃, C—CH₂CH₃, C—Cl or C—OCH₃ and Z is CH are also particularlypreferred.

Compounds of formula (Ixd) in which W is CH, X is C—OCH₂CH₃, Y is C—Fand Z is CH are also particularly preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—, and Zrepresents CH are also particularly preferred.

Compounds of formula (Ixd) in which W represents CH, X represents CR²and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—, and Zrepresents CH are also particularly preferred.

Compounds of formula (Ixd) in which X¹ is

and r is zero are especially preferred.

Compounds of formula (Ixd) in which W represents CH, X represents C—CH₃,Y represents C—CH₃ or C—Cl and Z represents CH are especially preferred.

Particular compounds of the invention of formula (Ix) are selected fromthe compounds formed by joining the carbon atom (C*) of one of thebenzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine orimidazo[4,5-b]pyrazine fragments (A1 to A110) shown in Table 1 to thecarbon atom (*C) in the heteroaryl moiety of one of the fragments (B1 toB168) shown in Table 2.

Particular compounds of the invention of formula (Ixa) are selected fromthe compounds formed by joining the carbon atom (C*) of one of thebenzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine orimidazo[4,5-b]pyrazine fragments (A1 to A110) shown in Table 1 to thecarbon atom (*C) in the pyrazole ring of one of the fragments (B1 toB48, B74 to B107, B124 to B127, 130 to 142 or 144 to 150) shown in Table2.

Particular compounds of the invention of formula (Ixb) are also selectedfrom the compounds formed by joining the carbon atom (C*) of one of thebenzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine orimidazo[4,5-b]pyrazine fragments (A1 to A110) shown in Table 1 to thecarbon atom (*C) in the five membered ring of one of the fragments (B63to B73, B108 to B114, B128 or B151) shown in Table 2.

Particular compounds of the invention of formula (Ixc) are selected fromthe compounds formed by joining the carbon atom (C*) of one of thebenzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine orimidazo[4,5-b]pyrazine fragments (A1 to A110) shown in Table 1 to thecarbon atom (*C) in the five membered ring of one of the fragments (B56,B59 or B129) shown in Table 2.

Particular compounds of the invention of formula (Ixd) are selected fromthe compounds formed by joining the carbon atom (C*) of one of thebenzoimidazole, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine orimidazo[4,5-b]pyrazine fragments (A1 to A110) shown in Table 1 to thecarbon atom (*C) in the five membered ring of one of the fragments (B115to B123 or B157) shown in Table 2. TABLE 1 A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

A67

A68

A69

A70

A71

A72

A73

A74

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

TABLE 2 B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

B20

B21

B22

B23

B24

B25

B26

B27

B28

B29

B30

B31

B32

B33

B34

B35

B36

B37

B38

B39

B40

B41

B42

B43

B44

B45

B46

B47

B48

B49

B50

B51

B52

B53

B54

B55

B56

B57

B58

B59

B60

B61

B62

B63

B64

B65

B66

B67

B68

B69

B70

B71

B72

B73

B74

B75

B76

B77

B78

B79

B80

B81

B82

B83

B84

B85

B86

B87

B88

B89

B90

B91

B92

B93

B94

B95

B96

B97

B98

B99

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

B116

B117

B118

B119

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B155

B156

B157

B158

B159

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

Particular compounds of the invention of formula (Ix) denoted as theproduct of the combination of group A1 to A110 in Table 1 with B1 toB169 in Table 2 are illustrated below: A1-B1; A1-B2; A1-B3; A1-B4;A1-B5; A1-B6; A1-B7; A1-B8; A1-B9; A1-B10; A1-B11; A1-B12; A1-B13;A1-B14; A1-B15; A1-B16; A1-B17; A1-B18; A1-B19; A1-B20; A1-B21; A1-B22;A1-B23; A1-B24; A1-B25; A1-B26; A1-B27; A1-B28; A1-B29; A1-B30; A1-B31;A1-B32; A1-B33; A1-B34; A1-B35; A1-B36; A1-B37; A1-B38; A1-B39; A1-B40;A1-B41; A1-B42; A1-B43; A1-B44; A1-B45; A1-B46; A1-B47; A1-B48; A1-B49;A1-B50; A1-B51; A1-B52; A1-B53; A1-B54; A1-B55; A1-B56; A1-B57; A1-B58;A1-B59; A1-B60; A1-B61; A1-B62; A1-B63; A1-B64; A1-B65; A1-B66; A1-B67;A1-B68; A1-B69; A1-B70; A1-B71; A1-B72; A1-B73; A1-B74; A1-B75; A1-B76;A1-B77; A1-B78; A1-B79; A1-B80; A1-B81; A1-B82; A1-B83; A1-B84; A1-B85;A1-B86; A1-B87; A1-B88; A1-B89; A1-B90; A1-B91; A1-B92; A1-B93; A1-B94;A1-B95; A1-B96; A1-B97; A1-B98; A1-B99; A1-B100; A1-B101; A1-B102;A1-B103; A1-B104; A1-B105; A1-B106; A1-B107; A1-B108; A1-B109; A1-B110;A1-B111; A1-B112; A1-B113; A1-B114; A1-B115; A1-B116; A1-B117; A1-B118;A1-B119; A1-B120; A1-B121; A1-B122; A1-B123; A1-B124; A1-B125; A1-B126;A1-B127; A1-B128; A1-B129; A1-B130; A1-B131; A1-B132; A1-B133; A1-B134;A1-B135; A1-B136; A1-B137; A1-B138; A1-B139; A1-B140; A1-B141; A1-B142;A1-B143; A1-B144; A1-B145; A1-B146; A1-B147; A1-B148; A1-B149; A1-B150;A1-B151; A1-B152; A1-B153; A1-B154; A1-B155; A1-B156; A1-B157; A1-B158;A1-B159; A1-B160; A1-B161; A1-B162; A1-B163; A1-B164; A1-B165; A1-B166;A1-B167; A1-B168; A1-B169; A2-B1; A2-B2; A2-B3; A2-B4; A2-B5; A2-B6;A2-B7; A2-B8; A2-B9; A2-B10; A2-B11; A2-B12; A2-B13; A2-B14; A2-B15;A2-B16; A2-B17; A2-B18; A2-B19; A2-B20; A2-B21; A2-B22; A2-B23; A2-B24;A2-B25; A2-B26; A2-B27; A2-B28; A2-B29; A2-B30; A2-B31; A2-B32; A2-B33;A2-B34; A2-B35; A2-B36; A2-B37; A2-B38; A2-B39; A2-B40; A2-B41; A2-B42;A2-B43; A2-B44; A2-B45; A2-B46; A2-B47; A2-B48; A2-B49; A2-B50; A2-B51;A2-B52; A2-B53; A2-B54; A2-B55; A2-B56; A2-B57; A2-B58; A2-B59; A2-B60;A2-B61; A2-B62; A2-B63; A2-B64; A2-B65; A2-B66; A2-B67; A2-B68; A2-B69;A2-B70; A2-B71; A2-B72; A2-B73; A2-B74; A2-B75; A2-B76; A2-B77; A2-B78;A2-B79; A2-B80; A2-B81; A2-B82; A2-B83; A2-B84; A2-B85; A2-B86; A2-B87;A2-B88; A2-B89; A2-B90; A2-B91; A2-B92; A2-B93; A2-B94; A2-B95; A2-B96;A2-B97; A2-B98; A2-B99; A2-B100; A2-B101; A2-B102; A2-B103; A2-B104;A2-B105; A2-B106; A2-B107; A2-B108; A2-B109; A2-B110; A2-B111; A2-B112;A2-B113; A2-B114; A2-B115; A2-B116; A2-B117; A2-B118; A2-B119; A2-B120;A2-B121; A2-B122; A2-B123; A2-B124; A2-B125; A2-B126; A2-B127; A2-B128;A2-B129; A2-B130; A2-B131; A2-B132; A2-B133; A2-B134; A2-B135; A2-B136;A2-B137; A2-B138; A2-B139; A2-B140; A2-B141; A2-B142; A2-B143; A2-B144;A2-B145; A2-B146; A2-B147; A2-B148; A2-B149; A2-B150; A2-B151; A2-B152;A2-B153; A2-B154; A2-B155; A2-B156; A2-B157; A2-B158; A2-B159; A2-B160;A2-B161; A2-B162; A2-B163; A2-B164; A2-B165; A2-B166; A2-B167; A2-B168;A2-B169; A3-B1; A3-B2; A3-B3; A3-B4; A3-B5; A3-B6; A3-B7; A3-B8; A3-B9;A3-B10; A3-B11; A3-B12; A3-B13; A3-B14; A3-B15; A3-B16; A3-B17; A3-B18;A3-B19; A3-B20; A3-B21; A3-B22; A3-B23; A3-B24; A3-B25; A3-B26; A3-B27;A3-B28; A3-B29; A3-B30; A3-B31; A3-B32; A3-B33; A3-B34; A3-B35; A3-B36;A3-B37; A3-B38; A3-B39; A3-B40; A3-B41; A3-B42; A3-B43; A3-B44; A3-B45;A3-B46; A3-B47; A3-B48; A3-B49; A3-B50; A3-B51; A3-B52; A3-B53; A3-B54;A3-B55; A3-B56; A3-B57; A3-B58; A3-B59; A3-B60; A3-B61; A3-B62; A3-B63;A3-B64; A3-B65; A3-B66; A3-B67; A3-B68; A3-B69; A3-B70; A3-B71; A3-B72;A3-B73; A3-B74; A3-B75; A3-B76; A3-B77; A3-B78; A3-B79; A3-B80; A3-B81;A3-B82; A3-B83; A3-B84; A3-B85; A3-B86; A3-B87; A3-B88; A3-B89; A3-B90;A3-B91; A3-B92; A3-B93; A3-B94; A3-B95; A3-B96; A3-B97; A3-B98; A3-B99;A3-B100; A3-B101; A3-B102; A3-B103; A3-B104; A3-B105; A3-B106; A3-B107;A3-B108; A3-B109; A3-B110; A3-B111; A3-B112; A3-B113; A3-B114; A3-B115;A3-B116; A3-B117; A3-B118; A3-B119; A3-B120; A3-B121; A3-B122; A3-B123;A3-B124; A3-B125; A3-B126; A3-B127; A3-B128; A3-B129; A3-B130; A3-B131;A3-B132; A3-B133; A3-B134; A3-B135; A3-B136; A3-B137; A3-B138; A3-B139;A3-B140; A3-B141; A3-B142; A3-B143; A3-B144; A3-B145; A3-B146; A3-B147;A3-B148; A3-B149; A3-B150; A3-B151; A3-B152; A3-B153; A3-B154; A3-B155;A3-B156; A3-B157; A3-B158; A3-B159; A3-B160; A3-B161; A3-B162; A3-B163;A3-B164; A3-B165; A3-B166; A3-B167; A3-B168; A3-B169; A4-B1; A4-B2;A4-B3; A4-B4; A4-B5; A4-B6; A4-B7; A4-B8; A4-B9; A4-B10; A4-B11; A4-B12;A4-B13; A4-B14; A4-B15; A4-B16; A4-B17; A4-B18; A4-B19; A4-B20; A4-B21;A4-B22; A4-B23; A4-B24; A4-B25; A4-B26; A4-B27; A4-B28; A4-B29; A4-B30;A4-B31; A4-B32; A4-B33; A4-B34; A4-B35; A4-B36; A4-B37; A4-B38; A4-B39;A4-B40; A4-B41; A4-B42; A4-B43; A4-B44; A4-B45; A4-B46; A4-B47; A4-B48;A4-B49; A4-B50; A4-B51; A4-B52; A4-B53; A4-B54; A4-B55; A4-B56; A4-B57;A4-B58; A4-B59; A4-B60; A4-B61; A4-B62; A4-B63; A4-B64; A4-B65; A4-B66;A4-B67; A4-B68; A4-B69; A4-B70; A4-B71; A4-B72; A4-B73; A4-B74; A4-B75;A4-B76; A4-B77; A4-B78; A4-B79; A4-B80; A4-B81; A4-B82; A4-B83; A4-B84;A4-B85; A4-B86; A4-B87; A4-B88; A4-B89; A4-B90; A4-B91; A4-B92; A4-B93;A4-B94; A4-B95; A4-B96; A4-B97; A4-B98; A4-B99; A4-B100; A4-B101;A4-B102; A4-B103; A4-B104; A4-B105; A4-B106; A4-B107; A4-B108; A4-B109;A4-B110; A4-B111; A4-B112; A4-B113; A4-B114; A4-B115; A4-B116; A4-B117;A4-B118; A4-B119; A4-B120; A4-B121; A4-B122; A4-B123; A4-B124; A4-B125;A4-B126; A4-B127; A4-B128; A4-B129; A4-B130; A4-B131; A4-B132; A4-B133;A4-B134; A4-B135; A4-B136; A4-B137; A4-B138; A4-B139; A4-B140; A4-B141;A4-B142; A4-B143; A4-B144; A4-B145; A4-B146; A4-B147; A4-B148; A4-B149;A4-B150; A4-B151; A4-B152; A4-B153; A4-B154; A4-B155; A4-B156; A4-B157;A4-B158; A4-B159; A4-B160; A4-B161; A4-B162; A4-B163; A4-B164; A4-B165;A4-B166; A4-B167; A4-B168; A4-B169; A5-B1; A5-B2; A5-B3; A5-B4; A5-B5;A5-B6; A5-B7; A5-B8; A5-B9; A5-B10; A5-B11; A5-B12; A5-B13; A5-B14;A5-B15; A5-B16; A5-B17; A5-B18; A5-B19; A5-B20; A5-B21; A5-B22; A5-B23;A5-B24; A5-B25; A5-B26; A5-B27; A5-B28; A5-B29; A5-B30; A5-B31; A5-B32;A5-B33; A5-B34; A5-B35; A5-B36; A5-B37; A5-B38; A5-B39; A5-B40; A5-B41;A5-B42; A5-B43; A5-B44; A5-B45; A5-B46; A5-B47; A5-B48; A5-B49; A5-B50;A5-B51; A5-B52; A5-B53; A5-B54; A5-B55; A5-B56; A5-B57; A5-B58; A5-B59;A5-B60; A5-B61; A5-B62; A5-B63; A5-B64; A5-B65; A5-B66; A5-B67; A5-B68;A5-B69; A5-B70; A5-B71; A5-B72; A5-B73; A5-B74; A5-B75; A5-B76; A5-B77;A5-B78; A5-B79; A5-B80; A5-B81; A5-B82; A5-B83; A5-B84; A5-B85; A5-B86;A5-B87; A5-B88; A5-B89; A5-B90; A5-B91; A5-B92; A5-B93; A5-B94; A5-B95;A5-B96; A5-B97; A5-B98; A5-B99; A5-B100; A5-B101; A5-B102; A5-B103;A5-B104; A5-B105; A5-B106; A5-B107; A5-B108; A5-B109; A5-B110; A5-B111;A5-B112; A5-B113; A5-B114; A5-B115; A5-B116; A5-B117; A5-B118; A5-B119;A5-B120; A5-B121; A5-B122; A5-B123; A5-B124; A5-B125; A5-B126; A5-B127;A5-B128; A5-B129; A5-B130; A5-B131; A5-B132; A5-B133; A5-B134; A5-B135;A5-B136; A5-B137; A5-B138; A5-B139; A5-B140; A5-B141; A5-B142; A5-B143;A5-B144; A5-B145; A5-B146; A5-B147; A5-B148; A5-B149; A5-B150; A5-B151;A5-B152; A5-B153; A5-B154; A5-B155; A5-B156; A5-B157; A5-B158; A5-B159;A5-B160; A5-B161; A5-B162; A5-B163; A5-B164; A5-B165; A5-B166; A5-B167;A5-B168; A5-B169; A6-B1; A6-B2; A6-B3; A6-B4; A6-B5; A6-B6; A6-B7;A6-B8; A6-B9; A6-B10; A6-B11; A6-B12; A6-B13; A6-B14; A6-B15; A6-B16;A6-B17; A6-B18; A6-B19; A6-B20; A6-B21; A6-B22; A6-B23; A6-B24; A6-B25;A6-B26; A6-B27; A6-B28; A6-B29; A6-B30; A6-B31; A6-B32; A6-B33; A6-B34;A6-B35; A6-B36; A6-B37; A6-B38; A6-B39; A6-B40; A6-B41; A6-B42; A6-B43;A6-B44; A6-B45; A6-B46; A6-B47; A6-B48; A6-B49; A6-B50; A6-B51; A6-B52;A6-B53; A6-B54; A6-B55; A6-B56; A6-B57; A6-B58; A6-B59; A6-B60; A6-B61;A6-B62; A6-B63; A6-B64; A6-B65; A6-B66; A6-B67; A6-B68; A6-B69; A6-B70;A6-B71; A6-B72; A6-B73; A6-B74; A6-B75; A6-B76; A6-B77; A6-B78; A6-B79;A6-B80; A6-B81; A6-B82; A6-B83; A6-B84; A6-B85; A6-B86; A6-B87; A6-B88;A6-B89; A6-B90; A6-B91; A6-B92; A6-B93; A6-B94; A6-B95; A6-B96; A6-B97;A6-B98; A6-B99; A6-B100; A6-B101; A6-B102; A6-B103; A6-B104; A6-B105;A6-B106; A6-B107; A6-B108; A6-B109; A6-B110; A6-B111; A6-B112; A6-B113;A6-B114; A6-B115; A6-B116; A6-B117; A6-B118; A6-B119; A6-B120; A6-B121;A6-B122; A6-B123; A6-B124; A6-B125; A6-B126; A6-B127; A6-B128; A6-B129;A6-B130; A6-B131; A6-B132; A6-B133; A6-B134; A6-B135; A6-B136; A6-B137;A6-B138; A6-B139; A6-B140; A6-B141; A6-B142; A6-B143; A6-B144; A6-B145;A6-B146; A6-B147; A6-B148; A6-B149; A6-B150; A6-B151; A6-B152; A6-B153;A6-B154; A6-B155; A6-B156; A6-B157; A6-B158; A6-B159; A6-B160; A6-B161;A6-B162; A6-B163; A6-B164; A6-B165; A6-B166; A6-B167; A6-B168; A6-B169;A7-B1; A7-B2; A7-B3; A7-B4; A7-B5; A7-B6; A7-B7; A7-B8; A7-B9; A7-B10;A7-B11; A7-B12; A7-B13; A7-B14; A7-B15; A7-B16; A7-B17; A7-B18; A7-B19;A7-B20; A7-B21; A7-B22; A7-B23; A7-B24; A7-B25; A7-B26; A7-B27; A7-B28;A7-B29; A7-B30; A7-B31; A7-B32; A7-B33; A7-B34; A7-B35; A7-B36; A7-B37;A7-B38; A7-B39; A7-B40; A7-B41; A7-B42; A7-B43; A7-B44; A7-B45; A7-B46;A7-B47; A7-B48; A7-B49; A7-B50; A7-B51; A7-B52; A7-B53; A7-B54; A7-B55;A7-B56; A7-B57; A7-B58; A7-B59; A7-B60; A7-B61; A7-B62; A7-B63; A7-B64;A7-B65; A7-B66; A7-B67; A7-B68; A7-B69; A7-B70; A7-B71; A7-B72; A7-B73;A7-B74; A7-B75; A7-B76; A7-B77; A7-B78; A7-B79; A7-B80; A7-B81; A7-B82;A7-B83; A7-B84; A7-B85; A7-B86; A7-B87; A7-B88; A7-B89; A7-B90; A7-B91;A7-B92; A7-B93; A7-B94; A7-B95; A7-B96; A7-B97; A7-B98; A7-B99; A7-B100;A7-B101; A7-B102; A7-B103; A7-B104; A7-B105; A7-B106; A7-B107; A7-B108;A7-B109; A7-B110; A7-B111; A7-B112; A7-B113; A7-B114; A7-B115; A7-B116;A7-B117; A7-B118; A7-B119; A7-B120; A7-B121; A7-B122; A7-B123; A7-B124;A7-B125; A7-B126; A7-B127; A7-B128; A7-B129; A7-B130; A7-B131; A7-B132;A7-B133; A7-B134; A7-B135; A7-B136; A7-B137; A7-B138; A7-B139; A7-B140;A7-B141; A7-B142; A7-B143; A7-B144; A7-B145; A7-B146; A7-B147; A7-B148;A7-B149; A7-B150; A7-B151; A7-B152; A7-B153; A7-B154; A7-B155; A7-B156;A7-B157; A7-B158; A7-B159; A7-B160; A7-B161; A7-B162; A7-B163; A7-B164;A7-B165; A7-B166; A7-B167; A7-B168; A7-B169; A8-B1; A8-B2; A8-B3; A8-B4;A8-B5; A8-B6; A8-B7; A8-B8; A8-B9; A8-B10; A8-B11; A8-B12; A8-B13;A8-B14; A8-B15; A8-B16; A8-B17; A8-B18; A8-B19; A8-B20; A8-B21; A8-B22;A8-B23; A8-B24; A8-B25; A8-B26; A8-B27; A8-B28; A8-B29; A8-B30; A8-B31;A8-B32; A8-B33; A8-B34; A8-B35; A8-B36; A8-B37; A8-B38; A8-B39; A8-B40;A8-B41; A8-B42; A8-B43; A8-B44; A8-B45; A8-B46; A8-B47; A8-B48; A8-B49;A8-B50; A8-B51; A8-B52; A8-B53; A8-B54; A8-B55; A8-B56; A8-B57; A8-B58;A8-B59; A8-B60; A8-B61; A8-B62; A8-B63; A8-B64; A8-B65; A8-B66; A8-B67;A8-B68; A8-B69; A8-B70; A8-B71; A8-B72; A8-B73; A8-B74; A8-B75; A8-B76;A8-B77; A8-B78; A8-B79; A8-B80; A8-B81; A8-B82; A8-B83; A8-B84; A8-B85;A8-B86; A8-B87; A8-B88; A8-B89; A8-B90; A8-B91; A8-B92; A8-B93; A8-B94;A8-B95; A8-B96; A8-B97; A8-B98; A8-B99; A8-B100; A8-B101; A8-B102;A8-B103; A8-B104; A8-B105; A8-B106; A8-B107; A8-B108; A8-B109; A8-B110;A8-B111; A8-B112; A8-B113; A8-B114; A8-B115; A8-B116; A8-B117; A8-B118;A8-B119; A8-B120; A8-B121; A8-B122; A8-B123; A8-B124; A8-B125; A8-B126;A8-B127; A8-B128; A8-B129; A8-B130; A8-B131; A8-B132; A8-B133; A8-B134;A8-B135; A8-B136; A8-B137; A8-B138; A8-B139; A8-B140; A8-B141; A8-B142;A8-B143; A8-B144; A8-B145; A8-B146; A8-B147; A8-B148; A8-B149; A8-B150;A8-B151; A8-B152; A8-B153; A8-B154; A8-B155; A8-B156; A8-B157; A8-B158;A8-B159; A8-B160; A8-B161; A8-B162; A8-B163; A8-B164; A8-B165; A8-B166;A8-B167; A8-B168; A8-B169; A9-B1; A9-B2; A9-B3; A9-B4; A9-B5; A9-B6;A9-B7; A9-B8; A9-B9; A9-B10; A9-B11; A9-B12; A9-B13; A9-B14; A9-B15;A9-B16; A9-B17; A9-B18; A9-B19; A9-B20; A9-B21; A9-B22; A9-B23; A9-B24;A9-B25; A9-B26; A9-B27; A9-B28; A9-B29; A9-B30; A9-B31; A9-B32; A9-B33;A9-B34; A9-B35; A9-B36; A9-B37; A9-B38; A9-B39; A9-B40; A9-B41; A9-B42;A9-B43; A9-B44; A9-B45; A9-B46; A9-B47; A9-B48; A9-B49; A9-B50; A9-B51;A9-B52; A9-B53; A9-B54; A9-B55; A9-B56; A9-B57; A9-B58; A9-B59; A9-B60;A9-B61; A9-B62; A9-B63; A9-B64; A9-B65; A9-B66; A9-B67; A9-B68; A9-B69;A9-B70; A9-B71; A9-B72; A9-B73; A9-B74; A9-B75; A9-B76; A9-B77; A9-B78;A9-B79; A9-B80; A9-B81; A9-B82; A9-B83; A9-B84; A9-B85; A9-B86; A9-B87;A9-B88; A9-B89; A9-B90; A9-B91; A9-B92; A9-B93; A9-B94; A9-B95; A9-B96;A9-B97; A9-B98; A9-B99; A9-B100; A9-B101; A9-B102; A9-B103; A9-B104;A9-B105; A9-B106; A9-B107; A9-B108; A9-B109; A9-B110; A9-B111; A9-B112;A9-B113; A9-B114; A9-B115; A9-B116; A9-B117; A9-B118; A9-B119; A9-B120;A9-B121; A9-B122; A9-B123; A9-B124; A9-B125; A9-B126; A9-B127; A9-B128;A9-B129; A9-B130; A9-B131; A9-B132; A9-B133; A9-B134; A9-B135; A9-B136;A9-B137; A9-B138; A9-B139; A9-B140; A9-B141; A9-B142; A9-B143; A9-B144;A9-B145; A9-B146; A9-B147; A9-B148; A9-B149; A9-B150; A9-B151; A9-B152;A9-B153; A9-B154; A9-B155; A9-B156; A9-B157; A9-B158; A9-B159; A9-B160;A9-B161; A9-B162; A9-B163; A9-B164; A9-B165; A9-B166; A9-B167; A9-B168;A9-B169; A10-B1; A10-B2; A10-B3; A10-B4; A10-B5; A10-B6; A10-B7; A10-B8;A10-B9; A10-B10; A10-B11; A10-B12; A10-B13; A10-B14; A10-B15; A10-B16;A10-B17; A10-B18; A10-B19; A10-B20; A10-B21; A10-B22; A10-B23; A10-B24;A10-B25; A10-B26; A10-B27; A10-B28; A10-B29; A10-B30; A10-B31; A10-B32;A10-B33; A10-B34; A10-B35; A10-B36; A10-B37; A10-B38; A10-B39; A10-B40;A10-B41; A10-B42; A10-B43; A10-B44; A10-B45; A10-B46; A10-B47; A10-B48;A10-B49; A10-B50; A10-B51; A10-B52; A10-B53; A10-B54; A10-B55; A10-B56;A10-B57; A10-B58; A10-B59; A10-B60; A10-B61; A10-B62; A10-B63; A10-B64;A10-B65; A10-B66; A10-B67; A10-B68; A10-B69; A10-B70; A10-B71; A10-B72;A10-B73; A10-B74; A10-B75; A10-B76; A10-B77; A10-B78; A10-B79; A10-B80;A10-B81; A10-B82; A10-B83; A10-B84; A10-B85; A10-B86; A10-B87; A10-B88;A10-B89; A10-B90; A10-B91; A10-B92; A10-B93; A10-B94; A10-B95; A10-B96;A10-B97; A10-B98; A10-B99; A10-B100; A10-B101; A10-B102; A10-B103;A10-B104; A10-B105; A10-B106; A10-B107; A10-B108; A10-B109; A10-B110;A10-B111; A10-B112; A10-B113; A10-B114; A10-B115; A10-B116; A10-B117;A10-B118; A10-B119; A10-B120; A10-B121; A10-B122; A10-B123; A10-B124;A10-B125; A10-B126; A10-B127; A10-B128; A10-B129; A10-B130; A10-B131;A10-B132; A10-B133; A10-B134; A10-B135; A10-B136; A10-B137; A10-B138;A10-B139; A10-B140; A10-B141; A10-B142; A10-B143; A10-B144; A10-B145;A10-B146; A10-B147; A10-B148; A10-B149; A10-B150; A10-B151; A10-B152;A10-B153; A10-B154; A10-B155; A10-B156; A10-B157; A10-B158; A10-B159;A10-B160; A10-B161; A10-B162; A10-B163; A10-B164; A10-B165; A10-B166;A10-B167; A10-B168; A10-B169; A11-B1; A11-B2; A11-B3; A11-B4; A11-B5;A11-B6; A11-B7; A11-B8; A11-B9; A11-B10; A11-B11; A11-B12; A11-B13;A11-B14; A11-B15; A11-B16; A11-B17; A11-B18; A11-B19; A11-B20; A11-B21;A11-B22; A11-B23; A11-B24; A11-B25; A11-B26; A11-B27; A11-B28; A11-B29;A11-B30; A11-B31; A11-B32; A11-B33; A11-B34; A11-B35; A11-B36; A11-B37;A11-B38; A11-B39; A11-B40; A11-B41; A11-B42; A11-B43; A11-B44; A11-B45;A11-B46; A11-B47; A11-B48; A11-B49; A11-B50; A11-B51; A11-B52; A11-B53;A11-B54; A11-B55; A11-B56; A11-B57; A11-B58; A11-B59; A11-B60; A11-B61;A11-B62; A11-B63; A11-B64; A11-B65; A11-B66; A11-B67; A11-B68; A11-B69;A11-B70; A11-B71; A11-B72; A11-B73; A11-B74; A11-B75; A11-B76; A11-B77;A11-B78; A11-B79; A11-B80; A11-B81; A11-B82; A11-B83; A11-B84; A11-B85;A11-B86; A11-B87; A11-B88; A11-B89; A11-B90; A11-B91; A11-B92; A11-B93;A11-B94; A11-B95; A11-B96; A11-B97; A11-B98; A11-B99; A11-B100;A11-B101; A11-B102; A11-B103; A11-B104; A11-B105; A11-B106; A11-B107;A11-B108; A11-B109; A11-B110; A11-B111; A11-B112; A11-B113; A11-B114;A11-B115; A11-B116; A11-B117; A11-B118; A11-B119; A11-B120; A11-B121;A11-B122; A11-B123; A11-B124; A11-B125; A11-B126; A11-B127; A11-B128;A11-B129; A11-B130; A11-B131; A11-B132; A11-B133; A11-B134; A11-B135;A11-B136; A11-B137; A11-B138; A11-B139; A11-B140; A11-B141; A11-B142;A11-B143; A11-B144; A11-B145; A11-B146; A11-B147; A11-B148; A11-B149;A11-B150; A11-B151; A11-B152; A11-B153; A11-B154; A11-B155; A11-B156;A11-B157; A11-B158; A11-B159; A11-B160; A11-B161; A11-B162; A11-B163;A11-B164; A11-B165; A11-B166; A11-B167; A11-B168; A11-B169; A12-B1;A12-B2; A12-B3; A12-B4; A12-B5; A12-B6; A12-B7; A12-B8; A12-B9; A12-B10;A12-B11; A12-B12; A12-B13; A12-B14; A12-B15; A12-B16; A12-B17; A12-B18;A12-B19; A12-B20; A12-B21; A12-B22; A12-B23; A12-B24; A12-B25; A12-B26;A12-B27; A12-B28; A12-B29; A12-B30; A12-B31; A12-B32; A12-B33; A12-B34;A12-B35; A12-B36; A12-B37; A12-B38; A12-B39; A12-B40; A12-B41; A12-B42;A12-B43; A12-B44; A12-B45; A12-B46; A12-B47; A12-B48; A12-B49; A12-B50;A12-B51; A12-B52; A12-B53; A12-B54; A12-B55; A12-B56; A12-B57; A12-B58;A12-B59; A12-B60; A12-B61; A12-B62; A12-B63; A12-B64; A12-B65; A12-B66;A12-B67; A12-B68; A12-B69; A12-B70; A12-B71; A12-B72; A12-B73; A12-B74;A12-B75; A12-B76; A12-B77; A12-B78; A12-B79; A12-B80; A12-B81; A12-B82;A12-B83; A12-B84; A12-B85; A12-B86; A12-B87; A12-B88; A12-B89; A12-B90;A12-B91; A12-B92; A12-B93; A12-B94; A12-B95; A12-B96; A12-B97; A12-B98;A12-B99; A12-B100; A12-B101; A12-B102; A12-B103; A12-B104; A12-B105;A12-B106; A12-B107; A12-B108; A12-B109; A12-B110; A12-B111; A12-B112;A12-B113; A12-B114; A12-B115; A12-B116; A12-B117; A12-B118; A12-B119;A12-B120; A12-B121; A12-B122; A12-B123; A12-B124; A12-B125; A12-B126;A12-B127; A12-B128; A12-B129; A12-B130; A12-B131; A12-B132; A12-B133;A12-B134; A12-B135; A12-B136; A12-B137; A12-B138; A12-B139; A12-B140;A12-B141; A12-B142; A12-B143; A12-B144; A12-B145; A12-B146; A12-B147;A12-B148; A12-B149; A12-B150; A12-B151; A12-B152; A12-B153; A12-B154;A12-B155; A12-B156; A12-B157; A12-B158; A12-B159; A12-B160; A12-B161;A12-B162; A12-B163; A12-B164; A12-B165; A12-B166; A12-B167; A12-B168;A12-B169; A13-B1; A13-B2; A13-B3; A13-B4; A13-B5; A13-B6; A13-B7;A13-B8; A13-B9; A13-B10; A13-B11; A13-B12; A13-B13; A13-B14; A13-B15;A13-B16; A13-B17; A13-B18; A13-B19; A13-B20; A13-B21; A13-B22; A13-B23;A13-B24; A13-B25; A13-B26; A13-B27; A13-B28; A13-B29; A13-B30; A13-B31;A13-B32; A13-B33; A13-B34; A13-B35; A13-B36; A13-B37; A13-B38; A13-B39;A13-B40; A13-B41; A13-B42; A13-B43; A13-B44; A13-B45; A13-B46; A13-B47;A13-B48; A13-B49; A13-B50; A13-B51; A13-B52; A13-B53; A13-B54; A13-B55;A13-B56; A13-B57; A13-B58; A13-B59; A13-B60; A13-B61; A13-B62; A13-B63;A13-B64; A13-B65; A13-B66; A13-B67; A13-B68; A13-B69; A13-B70; A13-B71;A13-B72; A13-B73; A13-B74; A13-B75; A13-B76; A13-B77; A13-B78; A13-B79;A13-B80; A13-B81; A13-B82; A13-B83; A13-B84; A13-B85; A13-B86; A13-B87;A13-B88; A13-B89; A13-B90; A13-B91; A13-B92; A13-B93; A13-B94; A13-B95;A13-B96; A13-B97; A13-B98; A13-B99; A13-B100; A13-B101; A13-B102;A13-B103; A13-B104; A13-B105; A13-B106; A13-B107; A13-B108; A13-B109;A13-B110; A13-B111; A13-B112; A13-B113; A13-B114; A13-B115; A13-B116;A13-B117; A13-B118; A13-B119; A13-B120; A13-B121; A13-B122; A13-B123;A13-B124; A13-B125; A13-B126; A13-B127; A13-B128; A13-B129; A13-B130;A13-B131; A13-B132; A13-B133; A13-B134; A13-B135; A13-B136; A13-B137;A13-B138; A13-B139; A13-B140; A13-B141; A13-B142; A13-B143; A13-B144;A13-B145; A13-B146; A13-B147; A13-B148; A13-B149; A13-B150; A13-B151;A13-B152; A13-B153; A13-B154; A13-B155; A13-B156; A13-B157; A13-B158;A13-B159; A13-B160; A13-B161; A13-B162; A13-B163; A13-B164; A13-B165;A13-B166; A13-B167; A13-B168; A13-B169; A14-B1; A14-B2; A14-B3; A14-B4;A14-B5; A14-B6; A14-B7; A14-B8; A14-B9; A14-B10; A14-B11; A14-B12;A14-B13; A14-B14; A14-B15; A14-B16; A14-B17; A14-B18; A14-B19; A14-B20;A14-B21; A14-B22; A14-B23; A14-B24; A14-B25; A14-B26; A14-B27; A14-B28;A14-B29; A14-B30; A14-B31; A14-B32; A14-B33; A14-B34; A14-B35; A14-B36;A14-B37; A14-B38; A14-B39; A14-B40; A14-B41; A14-B42; A14-B43; A14-B44;A14-B45; A14-B46; A14-B47; A14-B48; A14-B49; A14-B50; A14-B51; A14-B52;A14-B53; A14-B54; A14-B55; A14-B56; A14-B57; A14-B58; A14-B59; A14-B60;A14-B61; A14-B62; A14-B63; A14-B64; A14-B65; A14-B66; A14-B67; A14-B68;A14-B69; A14-B70; A14-B71; A14-B72; A14-B73; A14-B74; A14-B75; A14-B76;A14-B77; A14-B78; A14-B79; A14-B80; A14-B81; A14-B82; A14-B83; A14-B84;A14-B85; A14-B86; A14-B87; A14-B88; A14-B89; A14-B90; A14-B91; A14-B92;A14-B93; A14-B94; A14-B95; A14-B96; A14-B97; A14-B98; A14-B99; A14-B100;A14-B101; A14-B102; A14-B103; A14-B104; A14-B105; A14-B106; A14-B107;A14-B108; A14-B109; A14-B110; A14-B111; A14-B112; A14-B113; A14-B114;A14-B115; A14-B116; A14-B117; A14-B118; A14-B119; A14-B120; A14-B121;A14-B122; A14-B123; A14-B124; A14-B125; A14-B126; A14-B127; A14-B128;A14-B129; A14-B130; A14-B131; A14-B132; A14-B133; A14-B134; A14-B135;A14-B136; A14-B137; A14-B138; A14-B139; A14-B140; A14-B141; A14-B142;A14-B143; A14-B144; A14-B145; A14-B146; A14-B147; A14-B148; A14-B149;A14-B150; A14-B151; A14-B152; A14-B153; A14-B154; A14-B155; A14-B156;A14-B157; A14-B158; A14-B159; A14-B160; A14-B161; A14-B162; A14-B163;A14-B164; A14-B165; A14-B166; A14-B167; A14-B168; A14-B169; A15-B1;A15-B2; A15-B3; A15-B4; A15-B5; A15-B6; A15-B7; A15-B8; A15-B9; A15-B10;A15-B11; A15-B12; A15-B13; A15-B14; A15-B15; A15-B16; A15-B17; A15-B18;A15-B19; A15-B20; A15-B21; A15-B22; A15-B23; A15-B24; A15-B25; A15-B26;A15-B27; A15-B28; A15-B29; A15-B30; A15-B31; A15-B32; A15-B33; A15-B34;A15-B35; A15-B36; A15-B37; A15-B38; A15-B39; A15-B40; A15-B41; A15-B42;A15-B43; A15-B44; A15-B45; A15-B46; A15-B47; A15-B48; A15-B49; A15-B50;A15-B51; A15-B52; A15-B53; A15-B54; A15-B55; A15-B56; A15-B57; A15-B58;A15-B59; A15-B60; A15-B61; A15-B62; A15-B63; A15-B64; A15-B65; A15-B66;A15-B67; A15-B68; A15-B69; A15-B70; A15-B71; A15-B72; A15-B73; A15-B74;A15-B75; A15-B76; A15-B77; A15-B78; A15-B79; A15-B80; A15-B81; A15-B82;A15-B83; A15-B84; A15-B85; A15-B86; A15-B87; A15-B88; A15-B89; A15-B90;A15-B91; A15-B92; A15-B93; A15-B94; A15-B95; A15-B96; A15-B97; A15-B98;A15-B99; A15-B100; A15-B101; A15-B102; A15-B103; A15-B104; A15-B105;A15-B106; A15-B107; A15-B108; A15-B109; A15-B110; A15-B111; A15-B112;A15-B113; A15-B114; A15-B115; A15-B116; A15-B117; A15-B118; A15-B119;A15-B120; A15-B121; A15-B122; A15-B123; A15-B124; A15-B125; A15-B126;A15-B127; A15-B128; A15-B129; A15-B130; A15-B131; A15-B132; A15-B133;A15-B134; A15-B135; A15-B136; A15-B137; A15-B138; A15-B139; A15-B140;A15-B141; A15-B142; A15-B143; A15-B144; A15-B145; A15-B146; A15-B147;A15-B148; A15-B149; A15-B150; A15-B151; A15-B152; A15-B153; A15-B154;A15-B155; A15-B156; A15-B157; A15-B158; A15-B159; A15-B160; A15-B161;A15-B162; A15-B163; A15-B164; A15-B165; A15-B166; A15-B167; A15-B168;A15-B169; A16-B1; A16-B2; A16-B3; A16-B4; A16-B5; A16-B6; A16-B7;A16-B8; A16-B9; A16-B10; A16-B11; A16-B12; A16-B13; A16-B14; A16-B15;A16-B16; A16-B17; A16-B18; A16-B19; A16-B20; A16-B21; A16-B22; A16-B23;A16-B24; A16-B25; A16-B26; A16-B27; A16-B28; A16-B29; A16-B30; A16-B31;A16-B32; A16-B33; A16-B34; A16-B35; A16-B36; A16-B37; A16-B38; A16-B39;A16-B40; A16-B41; A16-B42; A16-B43; A16-B44; A16-B45; A16-B46; A16-B47;A16-B48; A16-B49; A16-B50; A16-B51; A16-B52; A16-B53; A16-B54; A16-B55;A16-B56; A16-B57; A16-B58; A16-B59; A16-B60; A16-B61; A16-B62; A16-B63;A16-B64; A16-B65; A16-B66; A16-B67; A16-B68; A16-B69; A16-B70; A16-B71;A16-B72; A16-B73; A16-B74; A16-B75; A16-B76; A16-B77; A16-B78; A16-B79;A16-B80; A16-B81; A16-B82; A16-B83; A16-B84; A16-B85; A16-B86; A16-B87;A16-B88; A16-B89; A16-B90; A16-B91; A16-B92; A16-B93; A16-B94; A16-B95;A16-B96; A16-B97; A16-B98; A16-B99; A16-B100; A16-B101; A16-B102;A16-B103; A16-B104; A16-B105; A16-B106; A16-B107; A16-B108; A16-B109;A16-B110; A16-B111; A16-B112; A16-B113; A16-B114; A16-B115; A16-B116;A16-B117; A16-B118; A16-B119; A16-B120; A16-B121; A16-B122; A16-B123;A16-B124; A16-B125; A16-B126; A16-B127; A16-B128; A16-B129; A16-B130;A16-B131; A16-B132; A16-B133; A16-B134; A16-B135; A16-B136; A16-B137;A16-B138; A16-B139; A16-B140; A16-B141; A16-B142; A16-B143; A16-B144;A16-B145; A16-B146; A16-B147; A16-B148; A16-B149; A16-B150; A16-B151;A16-B152; A16-B153; A16-B154; A16-B155; A16-B156; A16-B157; A16-B158;A16-B159; A16-B160; A16-B161; A16-B162; A16-B163; A16-B164; A16-B165;A16-B166; A16-B167; A16-B168; A16-B169; A17-B1; A17-B2; A17-B3; A17-B4;A17-B5; A17-B6; A17-B7; A17-B8; A17-B9; A17-B10; A17-B11; A17-B12;A17-B13; A17-B14; A17-B15; A17-B16; A17-B17; A17-B18; A17-B19; A17-B20;A17-B21; A17-B22; A17-B23; A17-B24; A17-B25; A17-B26; A17-B27; A17-B28;A17-B29; A17-B30; A17-B31; A17-B32; A17-B33; A17-B34; A17-B35; A17-B36;A17-B37; A17-B38; A17-B39; A17-B40; A17-B41; A17-B42; A17-B43; A17-B44;A17-B45; A17-B46; A17-B47; A17-B48; A17-B49; A17-B50; A17-B51; A17-B52;A17-B53; A17-B54; A17-B55; A17-B56; A17-B57; A17-B58; A17-B59; A17-B60;A17-B61; A17-B62; A17-B63; A17-B64; A17-B65; A17-B66; A17-B67; A17-B68;A17-B69; A17-B70; A17-B71; A17-B72; A17-B73; A17-B74; A17-B75; A17-B76;A17-B77; A17-B78; A17-B79; A17-B80; A17-B81; A17-B82; A17-B83; A17-B84;A17-B85; A17-B86; A17-B87; A17-B88; A17-B89; A17-B90; A17-B91; A17-B92;A17-B93; A17-B94; A17-B95; A17-B96; A17-B97; A17-B98; A17-B99; A17-B100;A17-B101; A17-B102; A17-B103; A17-B104; A17-B105; A17-B106; A17-B107;A17-B108; A17-B109; A17-B110; A17-B111; A17-B112; A17-B113; A17-B114;A17-B115; A17-B116; A17-B117; A17-B118; A17-B119; A17-B120; A17-B121;A17-B122; A17-B123; A17-B124; A17-B125; A17-B126; A17-B127; A17-B128;A17-B129; A17-B130; A17-B131; A17-B132; A17-B133; A17-B134; A17-B135;A17-B136; A17-B137; A17-B138; A17-B139; A17-B140; A17-B141; A17-B142;A17-B143; A17-B144; A17-B145; A17-B146; A17-B147; A17-B148; A17-B149;A17-B150; A17-B151; A17-B152; A17-B153; A17-B154; A17-B155; A17-B156;A17-B157; A17-B158; A17-B159; A17-B160; A17-B161; A17-B162; A17-B163;A17-B164; A17-B165; A17-B166; A17-B167; A17-B168; A17-B169; A18-B1;A18-B2; A18-B3; A18-B4; A18-B5; A18-B6; A18-B7; A18-B8; A18-B9; A18-B10;A18-B11; A18-B12; A18-B13; A18-B14; A18-B15; A18-B16; A18-B17; A18-B18;A18-B19; A18-B20; A18-B21; A18-B22; A18-B23; A18-B24; A18-B25; A18-B26;A18-B27; A18-B28; A18-B29; A18-B30; A18-B31; A18-B32; A18-B33; A18-B34;A18-B35; A18-B36; A18-B37; A18-B38; A18-B39; A18-B40; A18-B41; A18-B42;A18-B43; A18-B44; A18-B45; A18-B46; A18-B47; A18-B48; A18-B49; A18-B50;A18-B51; A18-B52; A18-B53; A18-B54; A18-B55; A18-B56; A18-B57; A18-B58;A18-B59; A18-B60; A18-B61; A18-B62; A18-B63; A18-B64; A18-B65; A18-B66;A18-B67; A18-B68; A18-B69; A18-B70; A18-B71; A18-B72; A18-B73; A18-B74;A18-B75; A18-B76; A18-B77; A18-B78; A18-B79; A18-B80; A18-B81; A18-B82;A18-B83; A18-B84; A18-B85; A18-B86; A18-B87; A18-B88; A18-B89; A18-B90;A18-B91; A18-B92; A18-B93; A18-B94; A18-B95; A18-B96; A18-B97; A18-B98;A18-B99; A18-B100; A18-B101; A18-B102; A18-B103; A18-B104; A18-B105;A18-B106; A18-B107; A18-B108; A18-B109; A18-B110; A18-B111; A18-B112;A18-B113; A18-B114; A18-B115; A18-B116; A18-B117; A18-B118; A18-B119;A18-B120; A18-B121; A18-B122; A18-B123; A18-B124; A18-B125; A18-B126;A18-B127; A18-B128; A18-B129; A18-B130; A18-B131; A18-B132; A18-B133;A18-B134; A18-B135; A18-B136; A18-B137; A18-B138; A18-B139; A18-B140;A18-B141; A18-B142; A18-B143; A18-B144; A18-B145; A18-B146; A18-B147;A18-B148; A18-B149; A18-B150; A18-B151; A18-B152; A18-B153; A18-B154;A18-B155; A18-B156; A18-B157; A18-B158; A18-B159; A18-B160; A18-B161;A18-B162; A18-B163; A18-B164; A18-B165; A18-B166; A18-B167; A18-B168;A18-B169; A19-B1; A19-B2; A19-B3; A19-B4; A19-B5; A19-B6; A19-B7;A19-B8; A19-B9; A19-B10; A19-B11; A19-B12; A19-B13; A19-B14; A19-B15;A19-B16; A19-B17; A19-B18; A19-B19; A19-B20; A19-B21; A19-B22; A19-B23;A19-B24; A19-B25; A19-B26; A19-B27; A19-B28; A19-B29; A19-B30; A19-B31;A19-B32; A19-B33; A19-B34; A19-B35; A19-B36; A19-B37; A19-B38; A19-B39;A19-B40; A19-B41; A19-B42; A19-B43; A19-B44; A19-B45; A19-B46; A19-B47;A19-B48; A19-B49; A19-B50; A19-B51; A19-B52; A19-B53; A19-B54; A19-B55;A19-B56; A19-B57; A19-B58; A19-B59; A19-B60; A19-B61; A19-B62; A19-B63;A19-B64; A19-B65; A19-B66; A19-B67; A19-B68; A19-B69; A19-B70; A19-B71;A19-B72; A19-B73; A19-B74; A19-B75; A19-B76; A19-B77; A19-B78; A19-B79;A19-B80; A19-B81; A19-B82; A19-B83; A19-B84; A19-B85; A19-B86; A19-B87;A19-B88; A19-B89; A19-B90; A19-B91; A19-B92; A19-B93; A19-B94; A19-B95;A19-B96; A19-B97; A19-B98; A19-B99; A19-B100; A19-B101; A19-B102;A19-B103; A19-B104; A19-B105; A19-B106; A19-B107; A19-B108; A19-B109;A19-B110; A19-B111; A19-B112; A19-B113; A19-B114; A19-B115; A19-B116;A19-B117; A19-B118; A19-B119; A19-B120; A19-B121; A19-B122; A19-B123;A19-B124; A19-B125; A19-B126; A19-B127; A19-B128; A19-B129; A19-B130;A19-B131; A19-B132; A19-B133; A19-B134; A19-B135; A19-B136; A19-B137;A19-B138; A19-B139; A19-B140; A19-B141; A19-B142; A19-B143; A19-B144;A19-B145; A19-B146; A19-B147; A19-B148; A19-B149; A19-B150; A19-B151;A19-B152; A19-B153; A19-B154; A19-B155; A19-B156; A19-B157; A19-B158;A19-B159; A19-B160; A19-B161; A19-B162; A19-B163; A19-B164; A19-B165;A19-B166; A19-B167; A19-B168; A19-B169; A20-B1; A20-B2; A20-B3; A20-B4;A20-B5; A20-B6; A20-B7; A20-B8; A20-B9; A20-B10; A20-B11; A20-B12;A20-B13; A20-B14; A20-B15; A20-B16; A20-B17; A20-B18; A20-B19; A20-B20;A20-B21; A20-B22; A20-B23; A20-B24; A20-B25; A20-B26; A20-B27; A20-B28;A20-B29; A20-B30; A20-B31; A20-B32; A20-B33; A20-B34; A20-B35; A20-B36;A20-B37; A20-B38; A20-B39; A20-B40; A20-B41; A20-B42; A20-B43; A20-B44;A20-B45; A20-B46; A20-B47; A20-B48; A20-B49; A20-B50; A20-B51; A20-B52;A20-B53; A20-B54; A20-B55; A20-B56; A20-B57; A20-B58; A20-B59; A20-B60;A20-B61; A20-B62; A20-B63; A20-B64; A20-B65; A20-B66; A20-B67; A20-B68;A20-B69; A20-B70; A20-B71; A20-B72; A20-B73; A20-B74; A20-B75; A20-B76;A20-B77; A20-B78; A20-B79; A20-B80; A20-B81; A20-B82; A20-B83; A20-B84;A20-B85; A20-B86; A20-B87; A20-B88; A20-B89; A20-B90; A20-B91; A20-B92;A20-B93; A20-B94; A20-B95; A20-B96; A20-B97; A20-B98; A20-B99; A20-B100;A20-B101; A20-B102; A20-B103; A20-B104; A20-B105; A20-B106; A20-B107;A20-B108; A20-B109; A20-B110; A20-B111; A20-B112; A20-B113; A20-B114;A20-B115; A20-B116; A20-B117; A20-B118; A20-B119; A20-B120; A20-B121;A20-B122; A20-B123; A20-B124; A20-B125; A20-B126; A20-B127; A20-B128;A20-B129; A20-B130; A20-B131; A20-B132; A20-B133; A20-B134; A20-B135;A20-B136; A20-B137; A20-B138; A20-B139; A20-B140; A20-B141; A20-B142;A20-B143; A20-B144; A20-B145; A20-B146; A20-B147; A20-B148; A20-B149;A20-B150; A20-B151; A20-B152; A20-B153; A20-B154; A20-B155; A20-B156;A20-B157; A20-B158; A20-B159; A20-B160; A20-B161; A20-B162; A20-B163;A20-B164; A20-B165; A20-B166; A20-B167; A20-B168; A20-B169; A21-B1;A21-B2; A21-B3; A21-B4; A21-B5; A21-B6; A21-B7; A21-B8; A21-B9; A21-B10;A21-B11; A21-B12; A21-B13; A21-B14; A21-B15; A21-B16; A21-B17; A21-B18;A21-B19; A21-B20; A21-B21; A21-B22; A21-B23; A21-B24; A21-B25; A21-B26;A21-B27; A21-B28; A21-B29; A21-B30; A21-B31; A21-B32; A21-B33; A21-B34;A21-B35; A21-B36; A21-B37; A21-B38; A21-B39; A21-B40; A21-B41; A21-B42;A21-B43; A21-B44; A21-B45; A21-B46; A21-B47; A21-B48; A21-B49; A21-B50;A21-B51; A21-B52; A21-B53; A21-B54; A21-B55; A21-B56; A21-B57; A21-B58;A21-B59; A21-B60; A21-B61; A21-B62; A21-B63; A21-B64; A21-B65; A21-B66;A21-B67; A21-B68; A21-B69; A21-B70; A21-B71; A21-B72; A21-B73; A21-B74;A21-B75; A21-B76; A21-B77; A21-B78; A21-B79; A21-B80; A21-B81; A21-B82;A21-B83; A21-B84; A21-B85; A21-B86; A21-B87; A21-B88; A21-B89; A21-B90;A21-B91; A21-B92; A21-B93; A21-B94; A21-B95; A21-B96; A21-B97; A21-B98;A21-B99; A21-B100; A21-B101; A21-B102; A21-B103; A21-B104; A21-B105;A21-B106; A21-B107; A21-B108; A21-B109; A21-B110; A21-B111; A21-B112;A21-B113; A21-B114; A21-B115; A21-B116; A21-B117; A21-B118; A21-B119;A21-B120; A21-B121; A21-B122; A21-B123; A21-B124; A21-B125; A21-B126;A21-B127; A21-B128; A21-B129; A21-B130; A21-B131; A21-B132; A21-B133;A21-B134; A21-B135; A21-B136; A21-B137; A21-B138; A21-B139; A21-B140;A21-B141; A21-B142; A21-B143; A21-B144; A21-B145; A21-B146; A21-B147;A21-B148; A21-B149; A21-B150; A21-B151; A21-B152; A21-B153; A21-B154;A21-B155; A21-B156; A21-B157; A21-B158; A21-B159; A21-B160; A21-B161;A21-B162; A21-B163; A21-B164; A21-B165; A21-B166; A21-B167; A21-B168;A21-B169; A22-B1; A22-B2; A22-B3; A22-B4; A22-B5; A22-B6; A22-B7;A22-B8; A22-B9; A22-B10; A22-B11; A22-B12; A22-B13; A22-B14; A22-B15;A22-B16; A22-B17; A22-B18; A22-B19; A22-B20; A22-B21; A22-B22; A22-B23;A22-B24; A22-B25; A22-B26; A22-B27; A22-B28; A22-B29; A22-B30; A22-B31;A22-B32; A22-B33; A22-B34; A22-B35; A22-B36; A22-B37; A22-B38; A22-B39;A22-B40; A22-B41; A22-B42; A22-B43; A22-B44; A22-B45; A22-B46; A22-B47;A22-B48; A22-B49; A22-B50; A22-B51; A22-B52; A22-B53; A22-B54; A22-B55;A22-B56; A22-B57; A22-B58; A22-B59; A22-B60; A22-B61; A22-B62; A22-B63;A22-B64; A22-B65; A22-B66; A22-B67; A22-B68; A22-B69; A22-B70; A22-B71;A22-B72; A22-B73; A22-B74; A22-B75; A22-B76; A22-B77; A22-B78; A22-B79;A22-B80; A22-B81; A22-B82; A22-B83; A22-B84; A22-B85; A22-B86; A22-B87;A22-B88; A22-B89; A22-B90; A22-B91; A22-B92; A22-B93; A22-B94; A22-B95;A22-B96; A22-B97; A22-B98; A22-B99; A22-B100; A22-B101; A22-B102;A22-B103; A22-B104; A22-B105; A22-B106; A22-B107; A22-B108; A22-B109;A22-B110; A22-B111; A22-B112; A22-B113; A22-B114; A22-B115; A22-B116;A22-B117; A22-B118; A22-B119; A22-B120; A22-B121; A22-B122; A22-B123;A22-B124; A22-B125; A22-B126; A22-B127; A22-B128; A22-B129; A22-B130;A22-B131; A22-B132; A22-B133; A22-B134; A22-B135; A22-B136; A22-B137;A22-B138; A22-B139; A22-B140; A22-B141; A22-B142; A22-B143; A22-B144;A22-B145; A22-B146; A22-B147; A22-B148; A22-B149; A22-B150; A22-B151;A22-B152; A22-B153; A22-B154; A22-B155; A22-B156; A22-B157; A22-B158;A22-B159; A22-B160; A22-B161; A22-B162; A22-B163; A22-B164; A22-B165;A22-B166; A22-B167; A22-B168; A22-B169; A23-B1; A23-B2; A23-B3; A23-B4;A23-B5; A23-B6; A23-B7; A23-B8; A23-B9; A23-B10; A23-B11; A23-B12;A23-B13; A23-B14; A23-B15; A23-B16; A23-B17; A23-B18; A23-B19; A23-B20;A23-B21; A23-B22; A23-B23; A23-B24; A23-B25; A23-B26; A23-B27; A23-B28;A23-B29; A23-B30; A23-B31; A23-B32; A23-B33; A23-B34; A23-B35; A23-B36;A23-B37; A23-B38; A23-B39; A23-B40; A23-B41; A23-B42; A23-B43; A23-B44;A23-B45; A23-B46; A23-B47; A23-B48; A23-B49; A23-B50; A23-B51; A23-B52;A23-B53; A23-B54; A23-B55; A23-B56; A23-B57; A23-B58; A23-B59; A23-B60;A23-B61; A23-B62; A23-B63; A23-B64; A23-B65; A23-B66; A23-B67; A23-B68;A23-B69; A23-B70; A23-B71; A23-B72; A23-B73; A23-B74; A23-B75; A23-B76;A23-B77; A23-B78; A23-B79; A23-B80; A23-B81; A23-B82; A23-B83; A23-B84;A23-B85; A23-B86; A23-B87; A23-B88; A23-B89; A23-B90; A23-B91; A23-B92;A23-B93; A23-B94; A23-B95; A23-B96; A23-B97; A23-B98; A23-B99; A23-B100;A23-B101; A23-B102; A23-B103; A23-B104; A23-B105; A23-B106; A23-B107;A23-B108; A23-B109; A23-B110; A23-B111; A23-B112; A23-B113; A23-B114;A23-B115; A23-B116; A23-B117; A23-B118; A23-B119; A23-B120; A23-B121;A23-B122; A23-B123; A23-B124; A23-B125; A23-B126; A23-B127; A23-B128;A23-B129; A23-B130; A23-B131; A23-B132; A23-B133; A23-B134; A23-B135;A23-B136; A23-B137; A23-B138; A23-B139; A23-B140; A23-B141; A23-B142;A23-B143; A23-B144; A23-B145; A23-B146; A23-B147; A23-B148; A23-B149;A23-B150; A23-B151; A23-B152; A23-B153; A23-B154; A23-B155; A23-B156;A23-B157; A23-B158; A23-B159; A23-B160; A23-B161; A23-B162; A23-B163;A23-B164; A23-B165; A23-B166; A23-B167; A23-B168; A23-B169; A24-B1;A24-B2; A24-B3; A24-B4; A24-B5; A24-B6; A24-B7; A24-B8; A24-B9; A24-B10;A24-B11; A24-B12; A24-B13; A24-B14; A24-B15; A24-B16; A24-B17; A24-B18;A24-B19; A24-B20; A24-B21; A24-B22; A24-B23; A24-B24; A24-B25; A24-B26;A24-B27; A24-B28; A24-B29; A24-B30; A24-B31; A24-B32; A24-B33; A24-B34;A24-B35; A24-B36; A24-B37; A24-B38; A24-B39; A24-B40; A24-B41; A24-B42;A24-B43; A24-B44; A24-B45; A24-B46; A24-B47; A24-B48; A24-B49; A24-B50;A24-B51; A24-B52; A24-B53; A24-B54; A24-B55; A24-B56; A24-B57; A24-B58;A24-B59; A24-B60; A24-B61; A24-B62; A24-B63; A24-B64; A24-B65; A24-B66;A24-B67; A24-B68; A24-B69; A24-B70; A24-B71; A24-B72; A24-B73; A24-B74;A24-B75; A24-B76; A24-B77; A24-B78; A24-B79; A24-B80; A24-B81; A24-B82;A24-B83; A24-B84; A24-B85; A24-B86; A24-B87; A24-B88; A24-B89; A24-B90;A24-B91; A24-B92; A24-B93; A24-B94; A24-B95; A24-B96; A24-B97; A24-B98;A24-B99; A24-B100; A24-B101; A24-B102; A24-B103; A24-B104; A24-B105;A24-B106; A24-B107; A24-B108; A24-B109; A24-B110; A24-B111; A24-B112;A24-B113; A24-B114; A24-B115; A24-B116; A24-B117; A24-B118; A24-B119;A24-B120; A24-B121; A24-B122; A24-B123; A24-B124; A24-B125; A24-B126;A24-B127; A24-B128; A24-B129; A24-B130; A24-B131; A24-B132; A24-B133;A24-B134; A24-B135; A24-B136; A24-B137; A24-B138; A24-B139; A24-B140;A24-B141; A24-B142; A24-B143; A24-B144; A24-B145; A24-B146; A24-B147;A24-B148; A24-B149; A24-B150; A24-B151; A24-B152; A24-B153; A24-B154;A24-B155; A24-B156; A24-B157; A24-B158; A24-B159; A24-B160; A24-B161;A24-B162; A24-B163; A24-B164; A24-B165; A24-B166; A24-B167; A24-B168;A24-B169; A25-B1; A25-B2; A25-B3; A25-B4; A25-B5; A25-B6; A25-B7;A25-B8; A25-B9; A25-B10; A25-B11; A25-B12; A25-B13; A25-B14; A25-B15;A25-B16; A25-B17; A25-B18; A25-B19; A25-B20; A25-B21; A25-B22; A25-B23;A25-B24; A25-B25; A25-B26; A25-B27; A25-B28; A25-B29; A25-B30; A25-B31;A25-B32; A25-B33; A25-B34; A25-B35; A25-B36; A25-B37; A25-B38; A25-B39;A25-B40; A25-B41; A25-B42; A25-B43; A25-B44; A25-B45; A25-B46; A25-B47;A25-B48; A25-B49; A25-B50; A25-B51; A25-B52; A25-B53; A25-B54; A25-B55;A25-B56; A25-B57; A25-B58; A25-B59; A25-B60; A25-B61; A25-B62; A25-B63;A25-B64; A25-B65; A25-B66; A25-B67; A25-B68; A25-B69; A25-B70; A25-B71;A25-B72; A25-B73; A25-B74; A25-B75; A25-B76; A25-B77; A25-B78; A25-B79;A25-B80; A25-B81; A25-B82; A25-B83; A25-B84; A25-B85; A25-B86; A25-B87;A25-B88; A25-B89; A25-B90; A25-B91; A25-B92; A25-B93; A25-B94; A25-B95;A25-B96; A25-B97; A25-B98; A25-B99; A25-B100; A25-B101; A25-B102;A25-B103; A25-B104; A25-B105; A25-B106; A25-B107; A25-B108; A25-B109;A25-B110; A25-B111; A25-B112; A25-B113; A25-B114; A25-B115; A25-B116;A25-B117; A25-B118; A25-B119; A25-B120; A25-B121; A25-B122; A25-B123;A25-B124; A25-B125; A25-B126; A25-B127; A25-B128; A25-B129; A25-B130;A25-B131; A25-B132; A25-B133; A25-B134; A25-B135; A25-B136; A25-B137;A25-B138; A25-B139; A25-B140; A25-B141; A25-B142; A25-B143; A25-B144;A25-B145; A25-B146; A25-B147; A25-B148; A25-B149; A25-B150; A25-B151;A25-B152; A25-B153; A25-B154; A25-B155; A25-B156; A25-B157; A25-B158;A25-B159; A25-B160; A25-B161; A25-B162; A25-B163; A25-B164; A25-B165;A25-B166; A25-B167; A25-B168; A25-B169; A26-B1; A26-B2; A26-B3; A26-B4;A26-B5; A26-B6; A26-B7; A26-B8; A26-B9; A26-B10; A26-B11; A26-B12;A26-B13; A26-B14; A26-B15; A26-B16; A26-B17; A26-B18; A26-B19; A26-B20;A26-B21; A26-B22; A26-B23; A26-B24; A26-B25; A26-B26; A26-B27; A26-B28;A26-B29; A26-B30; A26-B31; A26-B32; A26-B33; A26-B34; A26-B35; A26-B36;A26-B37; A26-B38; A26-B39; A26-B40; A26-B41; A26-B42; A26-B43; A26-B44;A26-B45; A26-B46; A26-B47; A26-B48; A26-B49; A26-B50; A26-B51; A26-B52;A26-B53; A26-B54; A26-B55; A26-B56; A26-B57; A26-B58; A26-B59; A26-B60;A26-B61; A26-B62; A26-B63; A26-B64; A26-B65; A26-B66; A26-B67; A26-B68;A26-B69; A26-B70; A26-B71; A26-B72; A26-B73; A26-B74; A26-B75; A26-B76;A26-B77; A26-B78; A26-B79; A26-B80; A26-B81; A26-B82; A26-B83; A26-B84;A26-B85; A26-B86; A26-B87; A26-B88; A26-B89; A26-B90; A26-B91; A26-B92;A26-B93; A26-B94; A26-B95; A26-B96; A26-B97; A26-B98; A26-B99; A26-B100;A26-B101; A26-B102; A26-B103; A26-B104; A26-B105; A26-B106; A26-B107;A26-B108; A26-B109; A26-B110; A26-B111; A26-B112; A26-B113; A26-B114;A26-B115; A26-B116; A26-B117; A26-B118; A26-B119; A26-B120; A26-B121;A26-B122; A26-B123; A26-B124; A26-B125; A26-B126; A26-B127; A26-B128;A26-B129; A26-B130; A26-B131; A26-B132; A26-B133; A26-B134; A26-B135;A26-B136; A26-B137; A26-B138; A26-B139; A26-B140; A26-B141; A26-B142;A26-B143; A26-B144; A26-B145; A26-B146; A26-B147; A26-B148; A26-B149;A26-B150; A26-B151; A26-B152; A26-B153; A26-B154; A26-B155; A26-B156;A26-B157; A26-B158; A26-B159; A26-B160; A26-B161; A26-B162; A26-B163;A26-B164; A26-B165; A26-B166; A26-B167; A26-B168; A26-B169; A27-B1;A27-B2; A27-B3; A27-B4; A27-B5; A27-B6; A27-B7; A27-B8; A27-B9; A27-B10;A27-B11; A27-B12; A27-B13; A27-B14; A27-B15; A27-B16; A27-B17; A27-B18;A27-B19; A27-B20; A27-B21; A27-B22; A27-B23; A27-B24; A27-B25; A27-B26;A27-B27; A27-B28; A27-B29; A27-B30; A27-B31; A27-B32; A27-B33; A27-B34;A27-B35; A27-B36; A27-B37; A27-B38; A27-B39; A27-B40; A27-B41; A27-B42;A27-B43; A27-B44; A27-B45; A27-B46; A27-B47; A27-B48; A27-B49; A27-B50;A27-B51; A27-B52; A27-B53; A27-B54; A27-B55; A27-B56; A27-B57; A27-B58;A27-B59; A27-B60; A27-B61; A27-B62; A27-B63; A27-B64; A27-B65; A27-B66;A27-B67; A27-B68; A27-B69; A27-B70; A27-B71; A27-B72; A27-B73; A27-B74;A27-B75; A27-B76; A27-B77; A27-B78; A27-B79; A27-B80; A27-B81; A27-B82;A27-B83; A27-B84; A27-B85; A27-B86; A27-B87; A27-B88; A27-B89; A27-B90;A27-B91; A27-B92; A27-B93; A27-B94; A27-B95; A27-B96; A27-B97; A27-B98;A27-B99; A27-B100; A27-B101; A27-B102; A27-B103; A27-B104; A27-B105;A27-B106; A27-B107; A27-B108; A27-B109; A27-B110; A27-B111; A27-B112;A27-B113; A27-B114; A27-B115; A27-B116; A27-B117; A27-B118; A27-B119;A27-B120; A27-B121; A27-B122; A27-B123; A27-B124; A27-B125; A27-B126;A27-B127; A27-B128; A27-B129; A27-B130; A27-B131; A27-B132; A27-B133;A27-B134; A27-B135; A27-B136; A27-B137; A27-B138; A27-B139; A27-B140;A27-B141; A27-B142; A27-B143; A27-B144; A27-B145; A27-B146; A27-B147;A27-B148; A27-B149; A27-B150; A27-B151; A27-B152; A27-B153; A27-B154;A27-B155; A27-B156; A27-B157; A27-B158; A27-B159; A27-B160; A27-B161;A27-B162; A27-B163; A27-B164; A27-B165; A27-B166; A27-B167; A27-B168;A27-B169; A28-B1; A28-B2; A28-B3; A28-B4; A28-B5; A28-B6; A28-B7;A28-B8; A28-B9; A28-B10; A28-B11; A28-B12; A28-B13; A28-B14; A28-B15;A28-B16; A28-B17; A28-B18; A28-B19; A28-B20; A28-B21; A28-B22; A28-B23;A28-B24; A28-B25; A28-B26; A28-B27; A28-B28; A28-B29; A28-B30; A28-B31;A28-B32; A28-B33; A28-B34; A28-B35; A28-B36; A28-B37; A28-B38; A28-B39;A28-B40; A28-B41; A28-B42; A28-B43; A28-B44; A28-B45; A28-B46; A28-B47;A28-B48; A28-B49; A28-B50; A28-B51; A28-B52; A28-B53; A28-B54; A28-B55;A28-B56; A28-B57; A28-B58; A28-B59; A28-B60; A28-B61; A28-B62; A28-B63;A28-B64; A28-B65; A28-B66; A28-B67; A28-B68; A28-B69; A28-B70; A28-B71;A28-B72; A28-B73; A28-B74; A28-B75; A28-B76; A28-B77; A28-B78; A28-B79;A28-B80; A28-B81; A28-B82; A28-B83; A28-B84; A28-B85; A28-B86; A28-B87;A28-B88; A28-B89; A28-B90; A28-B91; A28-B92; A28-B93; A28-B94; A28-B95;A28-B96; A28-B97; A28-B98; A28-B99; A28-B100; A28-B101; A28-B102;A28-B103; A28-B104; A28-B105; A28-B106; A28-B107; A28-B108; A28-B109;A28-B110; A28-B111; A28-B112; A28-B113; A28-B114; A28-B115; A28-B116;A28-B117; A28-B118; A28-B119; A28-B120; A28-B121; A28-B122; A28-B123;A28-B124; A28-B125; A28-B126; A28-B127; A28-B128; A28-B129; A28-B130;A28-B131; A28-B132; A28-B133; A28-B134; A28-B135; A28-B136; A28-B137;A28-B138; A28-B139; A28-B140; A28-B141; A28-B142; A28-B143; A28-B144;A28-B145; A28-B146; A28-B147; A28-B148; A28-B149; A28-B150; A28-B151;A28-B152; A28-B153; A28-B154; A28-B155; A28-B156; A28-B157; A28-B158;A28-B159; A28-B160; A28-B161; A28-B162; A28-B163; A28-B164; A28-B165;A28-B166; A28-B167; A28-B168; A28-B169; A29-B1; A29-B2; A29-B3; A29-B4;A29-B5; A29-B6; A29-B7; A29-B8; A29-B9; A29-B10; A29-B11; A29-B12;A29-B13; A29-B14; A29-B15; A29-B16; A29-B17; A29-B18; A29-B19; A29-B20;A29-B21; A29-B22; A29-B23; A29-B24; A29-B25; A29-B26; A29-B27; A29-B28;A29-B29; A29-B30; A29-B31; A29-B32; A29-B33; A29-B34; A29-B35; A29-B36;A29-B37; A29-B38; A29-B39; A29-B40; A29-B41; A29-B42; A29-B43; A29-B44;A29-B45; A29-B46; A29-B47; A29-B48; A29-B49; A29-B50; A29-B51; A29-B52;A29-B53; A29-B54; A29-B55; A29-B56; A29-B57; A29-B58; A29-B59; A29-B60;A29-B61; A29-B62; A29-B63; A29-B64; A29-B65; A29-B66; A29-B67; A29-B68;A29-B69; A29-B70; A29-B71; A29-B72; A29-B73; A29-B74; A29-B75; A29-B76;A29-B77; A29-B78; A29-B79; A29-B80; A29-B81; A29-B82; A29-B83; A29-B84;A29-B85; A29-B86; A29-B87; A29-B88; A29-B89; A29-B90; A29-B91; A29-B92;A29-B93; A29-B94; A29-B95; A29-B96; A29-B97; A29-B98; A29-B99; A29-B100;A29-B101; A29-B102; A29-B103; A29-B104; A29-B105; A29-B106; A29-B107;A29-B108; A29-B109; A29-B110; A29-B111; A29-B112; A29-B113; A29-B114;A29-B115; A29-B116; A29-B117; A29-B118; A29-B119; A29-B120; A29-B121;A29-B122; A29-B123; A29-B124; A29-B125; A29-B126; A29-B127; A29-B128;A29-B129; A29-B130; A29-B131; A29-B132; A29-B133; A29-B134; A29-B135;A29-B136; A29-B137; A29-B138; A29-B139; A29-B140; A29-B141; A29-B142;A29-B143; A29-B144; A29-B145; A29-B146; A29-B147; A29-B148; A29-B149;A29-B150; A29-B151; A29-B152; A29-B153; A29-B154; A29-B155; A29-B156;A29-B157; A29-B158; A29-B159; A29-B160; A29-B161; A29-B162; A29-B163;A29-B164; A29-B165; A29-B166; A29-B167; A29-B168; A29-B169; A30-B1;A30-B2; A30-B3; A30-B4; A30-B5; A30-B6; A30-B7; A30-B8; A30-B9; A30-B10;A30-B11; A30-B12; A30-B13; A30-B14; A30-B15; A30-B16; A30-B17; A30-B18;A30-B19; A30-B20; A30-B21; A30-B22; A30-B23; A30-B24; A30-B25; A30-B26;A30-B27; A30-B28; A30-B29; A30-B30; A30-B31; A30-B32; A30-B33; A30-B34;A30-B35; A30-B36; A30-B37; A30-B38; A30-B39; A30-B40; A30-B41; A30-B42;A30-B43; A30-B44; A30-B45; A30-B46; A30-B47; A30-B48; A30-B49; A30-B50;A30-B51; A30-B52; A30-B53; A30-B54; A30-B55; A30-B56; A30-B57; A30-B58;A30-B59; A30-B60; A30-B61; A30-B62; A30-B63; A30-B64; A30-B65; A30-B66;A30-B67; A30-B68; A30-B69; A30-B70; A30-B71; A30-B72; A30-B73; A30-B74;A30-B75; A30-B76; A30-B77; A30-B78; A30-B79; A30-B80; A30-B81; A30-B82;A30-B83; A30-B84; A30-B85; A30-B86; A30-B87; A30-B88; A30-B89; A30-B90;A30-B91; A30-B92; A30-B93; A30-B94; A30-B95; A30-B96; A30-B97; A30-B98;A30-B99; A30-B100; A30-B101; A30-B102; A30-B103; A30-B104; A30-B105;A30-B106; A30-B107; A30-B108; A30-B109; A30-B110; A30-B111; A30-B112;A30-B113; A30-B114; A30-B115; A30-B116; A30-B117; A30-B118; A30-B119;A30-B120; A30-B121; A30-B122; A30-B123; A30-B124; A30-B125; A30-B126;A30-B127; A30-B128; A30-B129; A30-B130; A30-B131; A30-B132; A30-B133;A30-B134; A30-B135; A30-B136; A30-B137; A30-B138; A30-B139; A30-B140;A30-B141; A30-B142; A30-B143; A30-B144; A30-B145; A30-B146; A30-B147;A30-B148; A30-B149; A30-B150; A30-B151; A30-B152; A30-B153; A30-B154;A30-B155; A30-B156; A30-B157; A30-B158; A30-B159; A30-B160; A30-B161;A30-B162; A30-B163; A30-B164; A30-B165; A30-B166; A30-B167; A30-B168;A30-B169; A31-B1; A31-B2; A31-B3; A31-B4; A31-B5; A31-B6; A31-B7;A31-B8; A31-B9; A31-B10; A31-B11; A31-B12; A31-B13; A31-B14; A31-B15;A31-B16; A31-B17; A31-B18; A31-B19; A31-B20; A31-B21; A31-B22; A31-B23;A31-B24; A31-B25; A31-B26; A31-B27; A31-B28; A31-B29; A31-B30; A31-B31;A31-B32; A31-B33; A31-B34; A31-B35; A31-B36; A31-B37; A31-B38; A31-B39;A31-B40; A31-B41; A31-B42; A31-B43; A31-B44; A31-B45; A31-B46; A31-B47;A31-B48; A31-B49; A31-B50; A31-B51; A31-B52; A31-B53; A31-B54; A31-B55;A31-B56; A31-B57; A31-B58; A31-B59; A31-B60; A31-B61; A31-B62; A31-B63;A31-B64; A31-B65; A31-B66; A31-B67; A31-B68; A31-B69; A31-B70; A31-B71;A31-B72; A31-B73; A31-B74; A31-B75; A31-B76; A31-B77; A31-B78; A31-B79;A31-B80; A31-B81; A31-B82; A31-B83; A31-B84; A31-B85; A31-B86; A31-B87;A31-B88; A31-B89; A31-B90; A31-B91; A31-B92; A31-B93; A31-B94; A31-B95;A31-B96; A31-B97; A31-B98; A31-B99; A31-B100; A31-B101; A31-B102;A31-B103; A31-B104; A31-B105; A31-B106; A31-B107; A31-B108; A31-B109;A31-B110; A31-B111; A31-B112; A31-B113; A31-B114; A31-B115; A31-B116;A31-B117; A31-B118; A31-B119; A31-B120; A31-B121; A31-B122; A31-B123;A31-B124; A31-B125; A31-B126; A31-B127; A31-B128; A31-B129; A31-B130;A31-B131; A31-B132; A31-B133; A31-B134; A31-B135; A31-B136; A31-B137;A31-B138; A31-B139; A31-B140; A31-B141; A31-B142; A31-B143; A31-B144;A31-B145; A31-B146; A31-B147; A31-B148; A31-B149; A31-B150; A31-B151;A31-B152; A31-B153; A31-B154; A31-B155; A31-B156; A31-B157; A31-B158;A31-B159; A31-B160; A31-B161; A31-B162; A31-B163; A31-B164; A31-B165;A31-B166; A31-B167; A31-B168; A31-B169; A32-B1; A32-B2; A32-B3; A32-B4;A32-B5; A32-B6; A32-B7; A32-B8; A32-B9; A32-B10; A32-B11; A32-B12;A32-B13; A32-B14; A32-B15; A32-B16; A32-B17; A32-B18; A32-B19; A32-B20;A32-B21; A32-B22; A32-B23; A32-B24; A32-B25; A32-B26; A32-B27; A32-B28;A32-B29; A32-B30; A32-B31; A32-B32; A32-B33; A32-B34; A32-B35; A32-B36;A32-B37; A32-B38; A32-B39; A32-B40; A32-B41; A32-B42; A32-B43; A32-B44;A32-B45; A32-B46; A32-B47; A32-B48; A32-B49; A32-B50; A32-B51; A32-B52;A32-B53; A32-B54; A32-B55; A32-B56; A32-B57; A32-B58; A32-B59; A32-B60;A32-B61; A32-B62; A32-B63; A32-B64; A32-B65; A32-B66; A32-B67; A32-B68;A32-B69; A32-B70; A32-B71; A32-B72; A32-B73; A32-B74; A32-B75; A32-B76;A32-B77; A32-B78; A32-B79; A32-B80; A32-B81; A32-B82; A32-B83; A32-B84;A32-B85; A32-B86; A32-B87; A32-B88; A32-B89; A32-B90; A32-B91; A32-B92;A32-B93; A32-B94; A32-B95; A32-B96; A32-B97; A32-B98; A32-B99; A32-B100;A32-B101; A32-B102; A32-B103; A32-B104; A32-B105; A32-B106; A32-B107;A32-B108; A32-B109; A32-B110; A32-B111; A32-B112; A32-B113; A32-B114;A32-B115; A32-B116; A32-B117; A32-B118; A32-B119; A32-B120; A32-B121;A32-B122; A32-B123; A32-B124; A32-B125; A32-B126; A32-B127; A32-B128;A32-B129; A32-B130; A32-B131; A32-B132; A32-B133; A32-B134; A32-B135;A32-B136; A32-B137; A32-B138; A32-B139; A32-B140; A32-B141; A32-B142;A32-B143; A32-B144; A32-B145; A32-B146; A32-B147; A32-B148; A32-B149;A32-B150; A32-B151; A32-B152; A32-B153; A32-B154; A32-B155; A32-B156;A32-B157; A32-B158; A32-B159; A32-B160; A32-B161; A32-B162; A32-B163;A32-B164; A32-B165; A32-B166; A32-B167; A32-B168; A32-B169; A33-B1;A33-B2; A33-B3; A33-B4; A33-B5; A33-B6; A33-B7; A33-B8; A33-B9; A33-B10;A33-B11; A33-B12; A33-B13; A33-B14; A33-B15; A33-B16; A33-B17; A33-B18;A33-B19; A33-B20; A33-B21; A33-B22; A33-B23; A33-B24; A33-B25; A33-B26;A33-B27; A33-B28; A33-B29; A33-B30; A33-B31; A33-B32; A33-B33; A33-B34;A33-B35; A33-B36; A33-B37; A33-B38; A33-B39; A33-B40; A33-B41; A33-B42;A33-B43; A33-B44; A33-B45; A33-B46; A33-B47; A33-B48; A33-B49; A33-B50;A33-B51; A33-B52; A33-B53; A33-B54; A33-B55; A33-B56; A33-B57; A33-B58;A33-B59; A33-B60; A33-B61; A33-B62; A33-B63; A33-B64; A33-B65; A33-B66;A33-B67; A33-B68; A33-B69; A33-B70; A33-B71; A33-B72; A33-B73; A33-B74;A33-B75; A33-B76; A33-B77; A33-B78; A33-B79; A33-B80; A33-B81; A33-B82;A33-B83; A33-B84; A33-B85; A33-B86; A33-B87; A33-B88; A33-B89; A33-B90;A33-B91; A33-B92; A33-B93; A33-B94; A33-B95; A33-B96; A33-B97; A33-B98;A33-B99; A33-B100; A33-B101; A33-B102; A33-B103; A33-B104; A33-B105;A33-B106; A33-B107; A33-B108; A33-B109; A33-B110; A33-B111; A33-B112;A33-B113; A33-B114; A33-B115; A33-B116; A33-B117; A33-B118; A33-B119;A33-B120; A33-B121; A33-B122; A33-B123; A33-B124; A33-B125; A33-B126;A33-B127; A33-B128; A33-B129; A33-B130; A33-B131; A33-B132; A33-B133;A33-B134; A33-B135; A33-B136; A33-B137; A33-B138; A33-B139; A33-B140;A33-B141; A33-B142; A33-B143; A33-B144; A33-B145; A33-B146; A33-B147;A33-B148; A33-B149; A33-B150; A33-B151; A33-B152; A33-B153; A33-B154;A33-B155; A33-B156; A33-B157; A33-B158; A33-B159; A33-B160; A33-B161;A33-B162; A33-B163; A33-B164; A33-B165; A33-B166; A33-B167; A33-B168;A33-B169; A34-B1; A34-B2; A34-B3; A34-B4; A34-B5; A34-B6; A34-B7;A34-B8; A34-B9; A34-B10; A34-B11; A34-B12; A34-B13; A34-B14; A34-B15;A34-B16; A34-B17; A34-B18; A34-B19; A34-B20; A34-B21; A34-B22; A34-B23;A34-B24; A34-B25; A34-B26; A34-B27; A34-B28; A34-B29; A34-B30; A34-B31;A34-B32; A34-B33; A34-B34; A34-B35; A34-B36; A34-B37; A34-B38; A34-B39;A34-B40; A34-B41; A34-B42; A34-B43; A34-B44; A34-B45; A34-B46; A34-B47;A34-B48; A34-B49; A34-B50; A34-B51; A34-B52; A34-B53; A34-B54; A34-B55;A34-B56; A34-B57; A34-B58; A34-B59; A34-B60; A34-B61; A34-B62; A34-B63;A34-B64; A34-B65; A34-B66; A34-B67; A34-B68; A34-B69; A34-B70; A34-B71;A34-B72; A34-B73; A34-B74; A34-B75; A34-B76; A34-B77; A34-B78; A34-B79;A34-B80; A34-B81; A34-B82; A34-B83; A34-B84; A34-B85; A34-B86; A34-B87;A34-B88; A34-B89; A34-B90; A34-B91; A34-B92; A34-B93; A34-B94; A34-B95;A34-B96; A34-B97; A34-B98; A34-B99; A34-B100; A34-B101; A34-B102;A34-B103; A34-B104; A34-B105; A34-B106; A34-B107; A34-B108; A34-B109;A34-B110; A34-B111; A34-B112; A34-B113; A34-B114; A34-B115; A34-B116;A34-B117; A34-B118; A34-B119; A34-B120; A34-B121; A34-B122; A34-B123;A34-B124; A34-B125; A34-B126; A34-B127; A34-B128; A34-B129; A34-B130;A34-B131; A34-B132; A34-B133; A34-B134; A34-B135; A34-B136; A34-B137;A34-B138; A34-B139; A34-B140; A34-B141; A34-B142; A34-B143; A34-B144;A34-B145; A34-B146; A34-B147; A34-B148; A34-B149; A34-B150; A34-B151;A34-B152; A34-B153; A34-B154; A34-B155; A34-B156; A34-B157; A34-B158;A34-B159; A34-B160; A34-B161; A34-B162; A34-B163; A34-B164; A34-B165;A34-B166; A34-B167; A34-B168; A34-B169; A35-B1; A35-B2; A35-B3; A35-B4;A35-B5; A35-B6; A35-B7; A35-B8; A35-B9; A35-B10; A35-B11; A35-B12;A35-B13; A35-B14; A35-B15; A35-B16; A35-B17; A35-B18; A35-B19; A35-B20;A35-B21; A35-B22; A35-B23; A35-B24; A35-B25; A35-B26; A35-B27; A35-B28;A35-B29; A35-B30; A35-B31; A35-B32; A35-B33; A35-B34; A35-B35; A35-B36;A35-B37; A35-B38; A35-B39; A35-B40; A35-B41; A35-B42; A35-B43; A35-B44;A35-B45; A35-B46; A35-B47; A35-B48; A35-B49; A35-B50; A35-B51; A35-B52;A35-B53; A35-B54; A35-B55; A35-B56; A35-B57; A35-B58; A35-B59; A35-B60;A35-B61; A35-B62; A35-B63; A35-B64; A35-B65; A35-B66; A35-B67; A35-B68;A35-B69; A35-B70; A35-B71; A35-B72; A35-B73; A35-B74; A35-B75; A35-B76;A35-B77; A35-B78; A35-B79; A35-B80; A35-B81; A35-B82; A35-B83; A35-B84;A35-B85; A35-B86; A35-B87; A35-B88; A35-B89; A35-B90; A35-B91; A35-B92;A35-B93; A35-B94; A35-B95; A35-B96; A35-B97; A35-B98; A35-B99; A35-B100;A35-B101; A35-B102; A35-B103; A35-B104; A35-B105; A35-B106; A35-B107;A35-B108; A35-B109; A35-B110; A35-B111; A35-B112; A35-B113; A35-B114;A35-B115; A35-B116; A35-B117; A35-B118; A35-B119; A35-B120; A35-B121;A35-B122; A35-B123; A35-B124; A35-B125; A35-B126; A35-B127; A35-B128;A35-B129; A35-B130; A35-B131; A35-B132; A35-B133; A35-B134; A35-B135;A35-B136; A35-B137; A35-B138; A35-B139; A35-B140; A35-B141; A35-B142;A35-B143; A35-B144; A35-B145; A35-B146; A35-B147; A35-B148; A35-B149;A35-B150; A35-B151; A35-B152; A35-B153; A35-B154; A35-B155; A35-B156;A35-B157; A35-B158; A35-B159; A35-B160; A35-B161; A35-B162; A35-B163;A35-B164; A35-B165; A35-B166; A35-B167; A35-B168; A35-B169; A36-B1;A36-B2; A36-B3; A36-B4; A36-B5; A36-B6; A36-B7; A36-B8; A36-B9; A36-B10;A36-B11; A36-B12; A36-B13; A36-B14; A36-B15; A36-B16; A36-B17; A36-B18;A36-B19; A36-B20; A36-B21; A36-B22; A36-B23; A36-B24; A36-B25; A36-B26;A36-B27; A36-B28; A36-B29; A36-B30; A36-B31; A36-B32; A36-B33; A36-B34;A36-B35; A36-B36; A36-B37; A36-B38; A36-B39; A36-B40; A36-B41; A36-B42;A36-B43; A36-B44; A36-B45; A36-B46; A36-B47; A36-B48; A36-B49; A36-B50;A36-B51; A36-B52; A36-B53; A36-B54; A36-B55; A36-B56; A36-B57; A36-B58;A36-B59; A36-B60; A36-B61; A36-B62; A36-B63; A36-B64; A36-B65; A36-B66;A36-B67; A36-B68; A36-B69; A36-B70; A36-B71; A36-B72; A36-B73; A36-B74;A36-B75; A36-B76; A36-B77; A36-B78; A36-B79; A36-B80; A36-B81; A36-B82;A36-B83; A36-B84; A36-B85; A36-B86; A36-B87; A36-B88; A36-B89; A36-B90;A36-B91; A36-B92; A36-B93; A36-B94; A36-B95; A36-B96; A36-B97; A36-B98;A36-B99; A36-B100; A36-B101; A36-B102; A36-B103; A36-B104; A36-B105;A36-B106; A36-B107; A36-B108; A36-B109; A36-B110; A36-B111; A36-B112;A36-B113; A36-B114; A36-B115; A36-B116; A36-B117; A36-B118; A36-B119;A36-B120; A36-B121; A36-B122; A36-B123; A36-B124; A36-B125; A36-B126;A36-B127; A36-B128; A36-B129; A36-B130; A36-B131; A36-B132; A36-B133;A36-B134; A36-B135; A36-B136; A36-B137; A36-B138; A36-B139; A36-B140;A36-B141; A36-B142; A36-B143; A36-B144; A36-B145; A36-B146; A36-B147;A36-B148; A36-B149; A36-B150; A36-B151; A36-B152; A36-B153; A36-B154;A36-B155; A36-B156; A36-B157; A36-B158; A36-B159; A36-B160; A36-B161;A36-B162; A36-B163; A36-B164; A36-B165; A36-B166; A36-B167; A36-B168;A36-B169; A37-B1; A37-B2; A37-B3; A37-B4; A37-B5; A37-B6; A37-B7;A37-B8; A37-B9; A37-B10; A37-B11; A37-B12; A37-B13; A37-B14; A37-B15;A37-B16; A37-B17; A37-B18; A37-B19; A37-B20; A37-B21; A37-B22; A37-B23;A37-B24; A37-B25; A37-B26; A37-B27; A37-B28; A37-B29; A37-B30; A37-B31;A37-B32; A37-B33; A37-B34; A37-B35; A37-B36; A37-B37; A37-B38; A37-B39;A37-B40; A37-B41; A37-B42; A37-B43; A37-B44; A37-B45; A37-B46; A37-B47;A37-B48; A37-B49; A37-B50; A37-B51; A37-B52; A37-B53; A37-B54; A37-B55;A37-B56; A37-B57; A37-B58; A37-B59; A37-B60; A37-B61; A37-B62; A37-B63;A37-B64; A37-B65; A37-B66; A37-B67; A37-B68; A37-B69; A37-B70; A37-B71;A37-B72; A37-B73; A37-B74; A37-B75; A37-B76; A37-B77; A37-B78; A37-B79;A37-B80; A37-B81; A37-B82; A37-B83; A37-B84; A37-B85; A37-B86; A37-B87;A37-B88; A37-B89; A37-B90; A37-B91; A37-B92; A37-B93; A37-B94; A37-B95;A37-B96; A37-B97; A37-B98; A37-B99; A37-B100; A37-B101; A37-B102;A37-B103; A37-B104; A37-B105; A37-B106; A37-B107; A37-B108; A37-B109;A37-B110; A37-B111; A37-B112; A37-B113; A37-B114; A37-B115; A37-B116;A37-B117; A37-B118; A37-B119; A37-B120; A37-B121; A37-B122; A37-B123;A37-B124; A37-B125; A37-B126; A37-B127; A37-B128; A37-B129; A37-B130;A37-B131; A37-B132; A37-B133; A37-B134; A37-B135; A37-B136; A37-B137;A37-B138; A37-B139; A37-B140; A37-B141; A37-B142; A37-B143; A37-B144;A37-B145; A37-B146; A37-B147; A37-B148; A37-B149; A37-B150; A37-B151;A37-B152; A37-B153; A37-B154; A37-B155; A37-B156; A37-B157; A37-B158;A37-B159; A37-B160; A37-B161; A37-B162; A37-B163; A37-B164; A37-B165;A37-B166; A37-B167; A37-B168; A37-B169; A38-B1; A38-B2; A38-B3; A38-B4;A38-B5; A38-B6; A38-B7; A38-B8; A38-B9; A38-B10; A38-B11; A38-B12;A38-B13; A38-B14; A38-B15; A38-B16; A38-B17; A38-B18; A38-B19; A38-B20;A38-B21; A38-B22; A38-B23; A38-B24; A38-B25; A38-B26; A38-B27; A38-B28;A38-B29; A38-B30; A38-B31; A38-B32; A38-B33; A38-B34; A38-B35; A38-B36;A38-B37; A38-B38; A38-B39; A38-B40; A38-B41; A38-B42; A38-B43; A38-B44;A38-B45; A38-B46; A38-B47; A38-B48; A38-B49; A38-B50; A38-B51; A38-B52;A38-B53; A38-B54; A38-B55; A38-B56; A38-B57; A38-B58; A38-B59; A38-B60;A38-B61; A38-B62; A38-B63; A38-B64; A38-B65; A38-B66; A38-B67; A38-B68;A38-B69; A38-B70; A38-B71; A38-B72; A38-B73; A38-B74; A38-B75; A38-B76;A38-B77; A38-B78; A38-B79; A38-B80; A38-B81; A38-B82; A38-B83; A38-B84;A38-B85; A38-B86; A38-B87; A38-B88; A38-B89; A38-B90; A38-B91; A38-B92;A38-B93; A38-B94; A38-B95; A38-B96; A38-B97; A38-B98; A38-B99; A38-B100;A38-B101; A38-B102; A38-B103; A38-B104; A38-B105; A38-B106; A38-B107;A38-B108; A38-B109; A38-B110; A38-B111; A38-B112; A38-B113; A38-B114;A38-B115; A38-B116; A38-B117; A38-B118; A38-B119; A38-B120; A38-B121;A38-B122; A38-B123; A38-B124; A38-B125; A38-B126; A38-B127; A38-B128;A38-B129; A38-B130; A38-B131; A38-B132; A38-B133; A38-B134; A38-B135;A38-B136; A38-B137; A38-B138; A38-B139; A38-B140; A38-B141; A38-B142;A38-B143; A38-B144; A38-B145; A38-B146; A38-B147; A38-B148; A38-B149;A38-B150; A38-B151; A38-B152; A38-B153; A38-B154; A38-B155; A38-B156;A38-B157; A38-B158; A38-B159; A38-B160; A38-B161; A38-B162; A38-B163;A38-B164; A38-B165; A38-B166; A38-B167; A38-B168; A38-B169; A39-B1;A39-B2; A39-B3; A39-B4; A39-B5; A39-B6; A39-B7; A39-B8; A39-B9; A39-B10;A39-B11; A39-B12; A39-B13; A39-B14; A39-B15; A39-B16; A39-B17; A39-B18;A39-B19; A39-B20; A39-B21; A39-B22; A39-B23; A39-B24; A39-B25; A39-B26;A39-B27; A39-B28; A39-B29; A39-B30; A39-B31; A39-B32; A39-B33; A39-B34;A39-B35; A39-B36; A39-B37; A39-B38; A39-B39; A39-B40; A39-B41; A39-B42;A39-B43; A39-B44; A39-B45; A39-B46; A39-B47; A39-B48; A39-B49; A39-B50;A39-B51; A39-B52; A39-B53; A39-B54; A39-B55; A39-B56; A39-B57; A39-B58;A39-B59; A39-B60; A39-B61; A39-B62; A39-B63; A39-B64; A39-B65; A39-B66;A39-B67; A39-B68; A39-B69; A39-B70; A39-B71; A39-B72; A39-B73; A39-B74;A39-B75; A39-B76; A39-B77; A39-B78; A39-B79; A39-B80; A39-B81; A39-B82;A39-B83; A39-B84; A39-B85; A39-B86; A39-B87; A39-B88; A39-B89; A39-B90;A39-B91; A39-B92; A39-B93; A39-B94; A39-B95; A39-B96; A39-B97; A39-B98;A39-B99; A39-B100; A39-B101; A39-B102; A39-B103; A39-B104; A39-B105;A39-B106; A39-B107; A39-B108; A39-B109; A39-B110; A39-B111; A39-B112;A39-B113; A39-B114; A39-B115; A39-B116; A39-B117; A39-B118; A39-B119;A39-B120; A39-B121; A39-B122; A39-B123; A39-B124; A39-B125; A39-B126;A39-B127; A39-B128; A39-B129; A39-B130; A39-B131; A39-B132; A39-B133;A39-B134; A39-B135; A39-B136; A39-B137; A39-B138; A39-B139; A39-B140;A39-B141; A39-B142; A39-B143; A39-B144; A39-B145; A39-B146; A39-B147;A39-B148; A39-B149; A39-B150; A39-B151; A39-B152; A39-B153; A39-B154;A39-B155; A39-B156; A39-B157; A39-B158; A39-B159; A39-B160; A39-B161;A39-B162; A39-B163; A39-B164; A39-B165; A39-B166; A39-B167; A39-B168;A39-B169; A40-B1; A40-B2; A40-B3; A40-B4; A40-B5; A40-B6; A40-B7;A40-B8; A40-B9; A40-B10; A40-B11; A40-B12; A40-B13; A40-B14; A40-B15;A40-B16; A40-B17; A40-B18; A40-B19; A40-B20; A40-B21; A40-B22; A40-B23;A40-B24; A40-B25; A40-B26; A40-B27; A40-B28; A40-B29; A40-B30; A40-B31;A40-B32; A40-B33; A40-B34; A40-B35; A40-B36; A40-B37; A40-B38; A40-B39;A40-B40; A40-B41; A40-B42; A40-B43; A40-B44; A40-B45; A40-B46; A40-B47;A40-B48; A40-B49; A40-B50; A40-B51; A40-B52; A40-B53; A40-B54; A40-B55;A40-B56; A40-B57; A40-B58; A40-B59; A40-B60; A40-B61; A40-B62; A40-B63;A40-B64; A40-B65; A40-B66; A40-B67; A40-B68; A40-B69; A40-B70; A40-B71;A40-B72; A40-B73; A40-B74; A40-B75; A40-B76; A40-B77; A40-B78; A40-B79;A40-B80; A40-B81; A40-B82; A40-B83; A40-B84; A40-B85; A40-B86; A40-B87;A40-B88; A40-B89; A40-B90; A40-B91; A40-B92; A40-B93; A40-B94; A40-B95;A40-B96; A40-B97; A40-B98; A40-B99; A40-B100; A40-B101; A40-B102;A40-B103; A40-B104; A40-B105; A40-B106; A40-B107; A40-B108; A40-B109;A40-B110; A40-B111; A40-B112; A40-B113; A40-B114; A40-B115; A40-B116;A40-B117; A40-B118; A40-B119; A40-B120; A40-B121; A40-B122; A40-B123;A40-B124; A40-B125; A40-B126; A40-B127; A40-B128; A40-B129; A40-B130;A40-B131; A40-B132; A40-B133; A40-B134; A40-B135; A40-B136; A40-B137;A40-B138; A40-B139; A40-B140; A40-B141; A40-B142; A40-B143; A40-B144;A40-B145; A40-B146; A40-B147; A40-B148; A40-B149; A40-B150; A40-B151;A40-B152; A40-B153; A40-B154; A40-B155; A40-B156; A40-B157; A40-B158;A40-B159; A40-B160; A40-B161; A40-B162; A40-B163; A40-B164; A40-B165;A40-B166; A40-B167; A40-B168; A40-B169; A41-B1; A41-B2; A41-B3; A41-B4;A41-B5; A41-B6; A41-B7; A41-B8; A41-B9; A41-B10; A41-B11; A41-B12;A41-B13; A41-B14; A41-B15; A41-B16; A41-B17; A41-B18; A41-B19; A41-B20;A41-B21; A41-B22; A41-B23; A41-B24; A41-B25; A41-B26; A41-B27; A41-B28;A41-B29; A41-B30; A41-B31; A41-B32; A41-B33; A41-B34; A41-B35; A41-B36;A41-B37; A41-B38; A41-B39; A41-B40; A41-B41; A41-B42; A41-B43; A41-B44;A41-B45; A41-B46; A41-B47; A41-B48; A41-B49; A41-B50; A41-B51; A41-B52;A41-B53; A41-B54; A41-B55; A41-B56; A41-B57; A41-B58; A41-B59; A41-B60;A41-B61; A41-B62; A41-B63; A41-B64; A41-B65; A41-B66; A41-B67; A41-B68;A41-B69; A41-B70; A41-B71; A41-B72; A41-B73; A41-B74; A41-B75; A41-B76;A41-B77; A41-B78; A41-B79; A41-B80; A41-B81; A41-B82; A41-B83; A41-B84;A41-B85; A41-B86; A41-B87; A41-B88; A41-B89; A41-B90; A41-B91; A41-B92;A41-B93; A41-B94; A41-B95; A41-B96; A41-B97; A41-B98; A41-B99; A41-B100;A41-B101; A41-B102; A41-B103; A41-B104; A41-B105; A41-B106; A41-B107;A41-B108; A41-B109; A41-B110; A41-B111; A41-B112; A41-B113; A41-B114;A41-B115; A41-B116; A41-B117; A41-B118; A41-B119; A41-B120; A41-B121;A41-B122; A41-B123; A41-B124; A41-B125; A41-B126; A41-B127; A41-B128;A41-B129; A41-B130; A41-B131; A41-B132; A41-B133; A41-B134; A41-B135;A41-B136; A41-B137; A41-B138; A41-B139; A41-B140; A41-B141; A41-B142;A41-B143; A41-B144; A41-B145; A41-B146; A41-B147; A41-B148; A41-B149;A41-B150; A41-B151; A41-B152; A41-B153; A41-B154; A41-B155; A41-B156;A41-B157; A41-B158; A41-B159; A41-B160; A41-B161; A41-B162; A41-B163;A41-B164; A41-B165; A41-B166; A41-B167; A41-B168; A41-B169; A42-B1;A42-B2; A42-B3; A42-B4; A42-B5; A42-B6; A42-B7; A42-B8; A42-B9; A42-B10;A42-B11; A42-B12; A42-B13; A42-B14; A42-B15; A42-B16; A42-B17; A42-B18;A42-B19; A42-B20; A42-B21; A42-B22; A42-B23; A42-B24; A42-B25; A42-B26;A42-B27; A42-B28; A42-B29; A42-B30; A42-B31; A42-B32; A42-B33; A42-B34;A42-B35; A42-B36; A42-B37; A42-B38; A42-B39; A42-B40; A42-B41; A42-B42;A42-B43; A42-B44; A42-B45; A42-B46; A42-B47; A42-B48; A42-B49; A42-B50;A42-B51; A42-B52; A42-B53; A42-B54; A42-B55; A42-B56; A42-B57; A42-B58;A42-B59; A42-B60; A42-B61; A42-B62; A42-B63; A42-B64; A42-B65; A42-B66;A42-B67; A42-B68; A42-B69; A42-B70; A42-B71; A42-B72; A42-B73; A42-B74;A42-B75; A42-B76; A42-B77; A42-B78; A42-B79; A42-B80; A42-B81; A42-B82;A42-B83; A42-B84; A42-B85; A42-B86; A42-B87; A42-B88; A42-B89; A42-B90;A42-B91; A42-B92; A42-B93; A42-B94; A42-B95; A42-B96; A42-B97; A42-B98;A42-B99; A42-B100; A42-B101; A42-B102; A42-B103; A42-B104; A42-B105;A42-B106; A42-B107; A42-B108; A42-B109; A42-B110; A42-B111; A42-B112;A42-B113; A42-B114; A42-B115; A42-B116; A42-B117; A42-B118; A42-B119;A42-B120; A42-B121; A42-B122; A42-B123; A42-B124; A42-B125; A42-B126;A42-B127; A42-B128; A42-B129; A42-B130; A42-B131; A42-B132; A42-B133;A42-B134; A42-B135; A42-B136; A42-B137; A42-B138; A42-B139; A42-B140;A42-B141; A42-B142; A42-B143; A42-B144; A42-B145; A42-B146; A42-B147;A42-B148; A42-B149; A42-B150; A42-B151; A42-B152; A42-B153; A42-B154;A42-B155; A42-B156; A42-B157; A42-B158; A42-B159; A42-B160; A42-B161;A42-B162; A42-B163; A42-B164; A42-B165; A42-B166; A42-B167; A42-B168;A42-B169; A43-B1; A43-B2; A43-B3; A43-B4; A43-B5; A43-B6; A43-B7;A43-B8; A43-B9; A43-B10; A43-B11; A43-B12; A43-B13; A43-B14; A43-B15;A43-B16; A43-B17; 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A44-B68;A44-B69; A44-B70; A44-B71; A44-B72; A44-B73; A44-B74; A44-B75; A44-B76;A44-B77; A44-B78; A44-B79; A44-B80; A44-B81; A44-B82; A44-B83; A44-B84;A44-B85; A44-B86; A44-B87; A44-B88; A44-B89; A44-B90; A44-B91; A44-B92;A44-B93; A44-B94; A44-B95; A44-B96; A44-B97; A44-B98; A44-B99; A44-B100;A44-B101; A44-B102; A44-B103; A44-B104; A44-B105; A44-B106; A44-B107;A44-B108; A44-B109; A44-B110; A44-B111; A44-B112; A44-B113; A44-B114;A44-B115; A44-B116; A44-B117; A44-B118; A44-B119; A44-B120; A44-B121;A44-B122; A44-B123; A44-B124; A44-B125; A44-B126; A44-B127; A44-B128;A44-B129; A44-B130; A44-B131; A44-B132; A44-B133; A44-B134; A44-B135;A44-B136; A44-B137; A44-B138; A44-B139; A44-B140; A44-B141; A44-B142;A44-B143; A44-B144; A44-B145; A44-B146; A44-B147; A44-B148; A44-B149;A44-B150; A44-B151; A44-B152; A44-B153; A44-B154; A44-B155; A44-B156;A44-B157; A44-B158; A44-B159; A44-B160; A44-B161; A44-B162; A44-B163;A44-B164; A44-B165; A44-B166; A44-B167; A44-B168; A44-B169; A45-B1;A45-B2; A45-B3; A45-B4; 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A46-B57; A46-B58; A46-B59; A46-B60; A46-B61; A46-B62; A46-B63;A46-B64; A46-B65; A46-B66; A46-B67; A46-B68; A46-B69; A46-B70; A46-B71;A46-B72; A46-B73; A46-B74; A46-B75; A46-B76; A46-B77; A46-B78; A46-B79;A46-B80; A46-B81; A46-B82; A46-B83; A46-B84; A46-B85; A46-B86; A46-B87;A46-B88; A46-B89; A46-B90; A46-B91; A46-B92; A46-B93; A46-B94; A46-B95;A46-B96; A46-B97; A46-B98; A46-B99; A46-B100; A46-B101; A46-B102;A46-B103; A46-B104; A46-B105; A46-B106; A46-B107; A46-B108; A46-B109;A46-B110; A46-B111; A46-B112; A46-B113; A46-B114; A46-B115; A46-B116;A46-B117; A46-B118; A46-B119; A46-B120; A46-B121; A46-B122; A46-B123;A46-B124; A46-B125; A46-B126; A46-B127; A46-B128; A46-B129; A46-B130;A46-B131; A46-B132; A46-B133; A46-B134; A46-B135; A46-B136; A46-B137;A46-B138; A46-B139; A46-B140; A46-B141; A46-B142; A46-B143; A46-B144;A46-B145; A46-B146; A46-B147; A46-B148; A46-B149; A46-B150; A46-B151;A46-B152; A46-B153; A46-B154; A46-B155; A46-B156; A46-B157; A46-B158;A46-B159; A46-B160; A46-B161; A46-B162; A46-B163; A46-B164; A46-B165;A46-B166; A46-B167; A46-B168; A46-B169; A47-B1; A47-B2; A47-B3; A47-B4;A47-B5; A47-B6; A47-B7; A47-B8; A47-B9; A47-B10; A47-B11; A47-B12;A47-B13; A47-B14; A47-B15; A47-B16; A47-B17; A47-B18; A47-B19; A47-B20;A47-B21; A47-B22; A47-B23; A47-B24; A47-B25; A47-B26; A47-B27; A47-B28;A47-B29; A47-B30; A47-B31; A47-B32; A47-B33; A47-B34; A47-B35; A47-B36;A47-B37; A47-B38; A47-B39; A47-B40; A47-B41; A47-B42; A47-B43; A47-B44;A47-B45; A47-B46; A47-B47; A47-B48; A47-B49; A47-B50; A47-B51; A47-B52;A47-B53; A47-B54; A47-B55; A47-B56; A47-B57; A47-B58; A47-B59; A47-B60;A47-B61; A47-B62; A47-B63; A47-B64; A47-B65; A47-B66; A47-B67; A47-B68;A47-B69; A47-B70; A47-B71; A47-B72; A47-B73; A47-B74; A47-B75; A47-B76;A47-B77; A47-B78; A47-B79; A47-B80; A47-B81; A47-B82; A47-B83; A47-B84;A47-B85; A47-B86; A47-B87; A47-B88; A47-B89; A47-B90; A47-B91; A47-B92;A47-B93; A47-B94; A47-B95; A47-B96; A47-B97; A47-B98; A47-B99; A47-B100;A47-B101; A47-B102; A47-B103; A47-B104; A47-B105; A47-B106; A47-B107;A47-B108; A47-B109; A47-B110; A47-B111; A47-B112; A47-B113; A47-B114;A47-B115; A47-B116; A47-B117; A47-B118; A47-B119; A47-B120; A47-B121;A47-B122; A47-B123; A47-B124; A47-B125; A47-B126; A47-B127; A47-B128;A47-B129; A47-B130; A47-B131; A47-B132; A47-B133; A47-B134; A47-B135;A47-B136; A47-B137; A47-B138; A47-B139; A47-B140; A47-B141; A47-B142;A47-B143; A47-B144; A47-B145; A47-B146; A47-B147; A47-B148; A47-B149;A47-B150; A47-B151; A47-B152; A47-B153; A47-B154; A47-B155; A47-B156;A47-B157; A47-B158; A47-B159; A47-B160; A47-B161; A47-B162; A47-B163;A47-B164; A47-B165; A47-B166; A47-B167; A47-B168; A47-B169; A48-B1;A48-B2; A48-B3; A48-B4; A48-B5; A48-B6; A48-B7; A48-B8; A48-B9; A48-B10;A48-B11; A48-B12; A48-B13; A48-B14; A48-B15; A48-B16; A48-B17; A48-B18;A48-B19; A48-B20; A48-B21; A48-B22; A48-B23; A48-B24; A48-B25; A48-B26;A48-B27; A48-B28; A48-B29; A48-B30; A48-B31; A48-B32; A48-B33; A48-B34;A48-B35; A48-B36; A48-B37; A48-B38; A48-B39; A48-B40; A48-B41; A48-B42;A48-B43; A48-B44; A48-B45; A48-B46; A48-B47; A48-B48; A48-B49; A48-B50;A48-B51; A48-B52; A48-B53; A48-B54; A48-B55; A48-B56; A48-B57; A48-B58;A48-B59; A48-B60; A48-B61; A48-B62; A48-B63; A48-B64; A48-B65; A48-B66;A48-B67; A48-B68; A48-B69; A48-B70; A48-B71; A48-B72; A48-B73; A48-B74;A48-B75; A48-B76; A48-B77; A48-B78; A48-B79; A48-B80; A48-B81; A48-B82;A48-B83; A48-B84; A48-B85; A48-B86; A48-B87; A48-B88; A48-B89; A48-B90;A48-B91; A48-B92; A48-B93; A48-B94; A48-B95; A48-B96; A48-B97; A48-B98;A48-B99; A48-B100; A48-B101; A48-B102; A48-B103; A48-B104; A48-B105;A48-B106; A48-B107; A48-B108; A48-B109; A48-B110; A48-B111; A48-B112;A48-B113; A48-B114; A48-B115; A48-B116; A48-B117; A48-B118; A48-B119;A48-B120; A48-B121; A48-B122; A48-B123; A48-B124; A48-B125; A48-B126;A48-B127; A48-B128; A48-B129; A48-B130; A48-B131; A48-B132; A48-B133;A48-B134; A48-B135; A48-B136; A48-B137; A48-B138; A48-B139; A48-B140;A48-B141; A48-B142; A48-B143; A48-B144; A48-B145; A48-B146; A48-B147;A48-B148; A48-B149; A48-B150; A48-B151; A48-B152; A48-B153; A48-B154;A48-B155; A48-B156; A48-B157; A48-B158; A48-B159; A48-B160; A48-B161;A48-B162; A48-B163; A48-B164; A48-B165; A48-B166; A48-B167; A48-B168;A48-B169; A49-B1; A49-B2; A49-B3; A49-B4; A49-B5; A49-B6; A49-B7;A49-B8; A49-B9; A49-B10; A49-B11; A49-B12; A49-B13; A49-B14; A49-B15;A49-B16; A49-B17; A49-B18; A49-B19; A49-B20; A49-B21; A49-B22; A49-B23;A49-B24; A49-B25; A49-B26; A49-B27; A49-B28; A49-B29; A49-B30; A49-B31;A49-B32; A49-B33; A49-B34; A49-B35; A49-B36; A49-B37; A49-B38; A49-B39;A49-B40; A49-B41; A49-B42; A49-B43; A49-B44; A49-B45; A49-B46; A49-B47;A49-B48; A49-B49; A49-B50; A49-B51; A49-B52; A49-B53; A49-B54; A49-B55;A49-B56; A49-B57; A49-B58; A49-B59; A49-B60; A49-B61; A49-B62; A49-B63;A49-B64; A49-B65; A49-B66; A49-B67; A49-B68; A49-B69; A49-B70; A49-B71;A49-B72; A49-B73; A49-B74; A49-B75; A49-B76; A49-B77; A49-B78; A49-B79;A49-B80; A49-B81; A49-B82; A49-B83; A49-B84; A49-B85; A49-B86; A49-B87;A49-B88; A49-B89; A49-B90; A49-B91; A49-B92; A49-B93; A49-B94; A49-B95;A49-B96; A49-B97; A49-B98; A49-B99; A49-B100; A49-B101; A49-B102;A49-B103; A49-B104; A49-B105; A49-B106; A49-B107; A49-B108; A49-B109;A49-B110; A49-B111; A49-B112; A49-B113; A49-B114; A49-B115; A49-B116;A49-B117; A49-B118; A49-B119; A49-B120; A49-B121; A49-B122; A49-B123;A49-B124; A49-B125; A49-B126; A49-B127; A49-B128; A49-B129; A49-B130;A49-B131; A49-B132; A49-B133; A49-B134; A49-B135; A49-B136; A49-B137;A49-B138; A49-B139; A49-B140; A49-B141; A49-B142; A49-B143; A49-B144;A49-B145; A49-B146; A49-B147; A49-B148; A49-B149; A49-B150; A49-B151;A49-B152; A49-B153; A49-B154; A49-B155; A49-B156; A49-B157; A49-B158;A49-B159; A49-B160; A49-B161; A49-B162; A49-B163; A49-B164; A49-B165;A49-B166; A49-B167; A49-B168; A49-B169; A50-B1; A50-B2; A50-B3; A50-B4;A50-B5; A50-B6; A50-B7; A50-B8; A50-B9; A50-B10; A50-B11; A50-B12;A50-B13; A50-B14; A50-B15; A50-B16; A50-B17; A50-B18; A50-B19; A50-B20;A50-B21; A50-B22; A50-B23; A50-B24; A50-B25; A50-B26; A50-B27; A50-B28;A50-B29; A50-B30; A50-B31; A50-B32; A50-B33; A50-B34; A50-B35; A50-B36;A50-B37; A50-B38; A50-B39; A50-B40; A50-B41; A50-B42; A50-B43; A50-B44;A50-B45; A50-B46; A50-B47; A50-B48; A50-B49; A50-B50; A50-B51; A50-B52;A50-B53; A50-B54; A50-B55; A50-B56; A50-B57; A50-B58; A50-B59; A50-B60;A50-B61; A50-B62; A50-B63; A50-B64; A50-B65; A50-B66; A50-B67; A50-B68;A50-B69; A50-B70; A50-B71; A50-B72; A50-B73; A50-B74; A50-B75; A50-B76;A50-B77; A50-B78; A50-B79; A50-B80; A50-B81; A50-B82; A50-B83; A50-B84;A50-B85; A50-B86; A50-B87; A50-B88; A50-B89; A50-B90; A50-B91; A50-B92;A50-B93; A50-B94; A50-B95; A50-B96; A50-B97; A50-B98; A50-B99; A50-B100;A50-B101; A50-B102; A50-B103; A50-B104; A50-B105; A50-B106; A50-B107;A50-B108; A50-B109; A50-B110; A50-B111; A50-B112; A50-B113; A50-B114;A50-B115; A50-B116; A50-B117; A50-B118; A50-B119; A50-B120; A50-B121;A50-B122; A50-B123; A50-B124; A50-B125; A50-B126; A50-B127; A50-B128;A50-B129; A50-B130; A50-B131; A50-B132; A50-B133; A50-B134; A50-B135;A50-B136; A50-B137; A50-B138; A50-B139; A50-B140; A50-B141; A50-B142;A50-B143; A50-B144; A50-B145; A50-B146; A50-B147; A50-B148; A50-B149;A50-B150; A50-B151; A50-B152; A50-B153; A50-B154; A50-B155; A50-B156;A50-B157; A50-B158; A50-B159; A50-B160; A50-B161; A50-B162; A50-B163;A50-B164; A50-B165; A50-B166; A50-B167; A50-B168; A50-B169; A51-B1;A51-B2; A51-B3; A51-B4; A51-B5; A51-B6; A51-B7; A51-B8; A51-B9; A51-B10;A51-B11; A51-B12; A51-B13; A51-B14; A51-B15; A51-B16; A51-B17; A51-B18;A51-B19; A51-B20; A51-B21; A51-B22; A51-B23; A51-B24; A51-B25; A51-B26;A51-B27; A51-B28; A51-B29; A51-B30; A51-B31; A51-B32; A51-B33; A51-B34;A51-B35; A51-B36; A51-B37; A51-B38; A51-B39; A51-B40; A51-B41; A51-B42;A51-B43; A51-B44; A51-B45; A51-B46; A51-B47; A51-B48; A51-B49; A51-B50;A51-B51; A51-B52; A51-B53; A51-B54; A51-B55; A51-B56; A51-B57; A51-B58;A51-B59; A51-B60; A51-B61; A51-B62; A51-B63; A51-B64; A51-B65; A51-B66;A51-B67; A51-B68; A51-B69; A51-B70; A51-B71; A51-B72; A51-B73; A51-B74;A51-B75; A51-B76; A51-B77; A51-B78; A51-B79; A51-B80; A51-B81; A51-B82;A51-B83; A51-B84; A51-B85; A51-B86; A51-B87; A51-B88; A51-B89; A51-B90;A51-B91; A51-B92; A51-B93; A51-B94; A51-B95; A51-B96; A51-B97; A51-B98;A51-B99; A51-B100; A51-B101; A51-B102; A51-B103; A51-B104; A51-B105;A51-B106; A51-B107; A51-B108; A51-B109; A51-B110; A51-B111; A51-B112;A51-B113; A51-B114; A51-B115; A51-B116; A51-B117; A51-B118; A51-B119;A51-B120; A51-B121; A51-B122; A51-B123; A51-B124; A51-B125; A51-B126;A51-B127; A51-B128; A51-B129; A51-B130; A51-B131; A51-B132; A51-B133;A51-B134; A51-B135; A51-B136; A51-B137; A51-B138; A51-B139; A51-B140;A51-B141; A51-B142; A51-B143; A51-B144; A51-B145; A51-B146; A51-B147;A51-B148; A51-B149; A51-B150; A51-B151; A51-B152; A51-B153; A51-B154;A51-B155; A51-B156; A51-B157; A51-B158; A51-B159; A51-B160; A51-B161;A51-B162; A51-B163; A51-B164; A51-B165; A51-B166; A51-B167; A51-B168;A51-B169; A52-B1; A52-B2; A52-B3; A52-B4; A52-B5; A52-B6; A52-B7;A52-B8; A52-B9; A52-B10; A52-B11; A52-B12; A52-B13; A52-B14; A52-B15;A52-B16; A52-B17; A52-B18; A52-B19; A52-B20; 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A52-B132; A52-B133; A52-B134; A52-B135; A52-B136; A52-B137;A52-B138; A52-B139; A52-B140; A52-B141; A52-B142; A52-B143; A52-B144;A52-B145; A52-B146; A52-B147; A52-B148; A52-B149; A52-B150; A52-B151;A52-B152; A52-B153; A52-B154; A52-B155; A52-B156; A52-B157; A52-B158;A52-B159; A52-B160; A52-B161; A52-B162; A52-B163; A52-B164; A52-B165;A52-B166; A52-B167; A52-B168; A52-B169; A53-B1; A53-B2; A53-B3; A53-B4;A53-B5; A53-B6; A53-B7; A53-B8; A53-B9; A53-B10; A53-B11; A53-B12;A53-B13; A53-B14; A53-B15; A53-B16; A53-B17; A53-B18; A53-B19; A53-B20;A53-B21; A53-B22; A53-B23; A53-B24; A53-B25; A53-B26; A53-B27; A53-B28;A53-B29; A53-B30; A53-B31; A53-B32; A53-B33; A53-B34; A53-B35; A53-B36;A53-B37; A53-B38; A53-B39; A53-B40; A53-B41; A53-B42; A53-B43; A53-B44;A53-B45; A53-B46; A53-B47; A53-B48; A53-B49; A53-B50; A53-B51; A53-B52;A53-B53; A53-B54; A53-B55; A53-B56; A53-B57; A53-B58; A53-B59; A53-B60;A53-B61; A53-B62; A53-B63; A53-B64; A53-B65; A53-B66; A53-B67; A53-B68;A53-B69; A53-B70; A53-B71; A53-B72; A53-B73; A53-B74; A53-B75; A53-B76;A53-B77; A53-B78; A53-B79; A53-B80; A53-B81; A53-B82; A53-B83; A53-B84;A53-B85; A53-B86; A53-B87; A53-B88; A53-B89; A53-B90; A53-B91; A53-B92;A53-B93; A53-B94; A53-B95; A53-B96; A53-B97; A53-B98; A53-B99; A53-B100;A53-B101; A53-B102; A53-B103; A53-B104; A53-B105; A53-B106; A53-B107;A53-B108; A53-B109; A53-B110; A53-B111; A53-B112; A53-B113; A53-B114;A53-B115; A53-B116; A53-B117; A53-B118; A53-B119; A53-B120; A53-B121;A53-B122; A53-B123; A53-B124; A53-B125; A53-B126; A53-B127; A53-B128;A53-B129; A53-B130; A53-B131; A53-B132; A53-B133; A53-B134; A53-B135;A53-B136; A53-B137; A53-B138; A53-B139; A53-B140; A53-B141; A53-B142;A53-B143; A53-B144; A53-B145; A53-B146; A53-B147; A53-B148; A53-B149;A53-B150; A53-B151; A53-B152; A53-B153; A53-B154; A53-B155; A53-B156;A53-B157; A53-B158; A53-B159; A53-B160; A53-B161; A53-B162; A53-B163;A53-B164; A53-B165; A53-B166; A53-B167; A53-B168; A53-B169; A54-B1;A54-B2; A54-B3; A54-B4; A54-B5; A54-B6; A54-B7; A54-B8; A54-B9; A54-B10;A54-B11; A54-B12; A54-B13; A54-B14; A54-B15; A54-B16; A54-B17; A54-B18;A54-B19; A54-B20; A54-B21; A54-B22; A54-B23; A54-B24; A54-B25; A54-B26;A54-B27; A54-B28; A54-B29; A54-B30; A54-B31; A54-B32; A54-B33; A54-B34;A54-B35; A54-B36; A54-B37; A54-B38; A54-B39; A54-B40; A54-B41; A54-B42;A54-B43; A54-B44; A54-B45; A54-B46; A54-B47; A54-B48; A54-B49; A54-B50;A54-B51; A54-B52; A54-B53; A54-B54; A54-B55; A54-B56; A54-B57; A54-B58;A54-B59; A54-B60; A54-B61; A54-B62; A54-B63; A54-B64; A54-B65; A54-B66;A54-B67; A54-B68; A54-B69; A54-B70; A54-B71; A54-B72; A54-B73; A54-B74;A54-B75; A54-B76; A54-B77; A54-B78; A54-B79; A54-B80; A54-B81; A54-B82;A54-B83; A54-B84; A54-B85; A54-B86; A54-B87; A54-B88; A54-B89; A54-B90;A54-B91; A54-B92; A54-B93; A54-B94; A54-B95; A54-B96; A54-B97; A54-B98;A54-B99; A54-B100; A54-B101; A54-B102; A54-B103; A54-B104; A54-B105;A54-B106; A54-B107; A54-B108; A54-B109; A54-B110; A54-B111; A54-B112;A54-B113; A54-B114; A54-B115; A54-B116; A54-B117; A54-B118; A54-B119;A54-B120; A54-B121; A54-B122; A54-B123; A54-B124; A54-B125; A54-B126;A54-B127; A54-B128; A54-B129; A54-B130; A54-B131; A54-B132; A54-B133;A54-B134; A54-B135; A54-B136; A54-B137; A54-B138; A54-B139; A54-B140;A54-B141; A54-B142; A54-B143; A54-B144; A54-B145; A54-B146; A54-B147;A54-B148; A54-B149; A54-B150; A54-B151; A54-B152; A54-B153; A54-B154;A54-B155; A54-B156; A54-B157; A54-B158; A54-B159; A54-B160; A54-B161;A54-B162; A54-B163; A54-B164; A54-B165; A54-B166; A54-B167; A54-B168;A54-B169; A55-B1; A55-B2; A55-B3; A55-B4; A55-B5; A55-B6; A55-B7;A55-B8; A55-B9; A55-B10; A55-B11; A55-B12; A55-B13; A55-B14; A55-B15;A55-B16; A55-B17; A55-B18; A55-B19; A55-B20; A55-B21; A55-B22; A55-B23;A55-B24; A55-B25; A55-B26; A55-B27; A55-B28; A55-B29; A55-B30; A55-B31;A55-B32; A55-B33; A55-B34; A55-B35; A55-B36; A55-B37; A55-B38; A55-B39;A55-B40; A55-B41; A55-B42; A55-B43; A55-B44; A55-B45; A55-B46; A55-B47;A55-B48; A55-B49; A55-B50; A55-B51; A55-B52; A55-B53; A55-B54; A55-B55;A55-B56; A55-B57; A55-B58; A55-B59; A55-B60; A55-B61; A55-B62; A55-B63;A55-B64; A55-B65; A55-B66; A55-B67; A55-B68; A55-B69; A55-B70; A55-B71;A55-B72; A55-B73; A55-B74; A55-B75; A55-B76; A55-B77; A55-B78; A55-B79;A55-B80; A55-B81; A55-B82; A55-B83; A55-B84; A55-B85; A55-B86; A55-B87;A55-B88; A55-B89; A55-B90; A55-B91; A55-B92; A55-B93; A55-B94; A55-B95;A55-B96; A55-B97; A55-B98; A55-B99; A55-B100; A55-B101; A55-B102;A55-B103; A55-B104; A55-B105; A55-B106; A55-B107; A55-B108; A55-B109;A55-B110; A55-B111; A55-B112; A55-B113; A55-B114; A55-B115; A55-B116;A55-B117; A55-B118; A55-B119; A55-B120; A55-B121; A55-B122; A55-B123;A55-B124; A55-B125; A55-B126; A55-B127; A55-B128; A55-B129; A55-B130;A55-B131; A55-B132; A55-B133; A55-B134; A55-B135; A55-B136; A55-B137;A55-B138; A55-B139; A55-B140; A55-B141; A55-B142; A55-B143; A55-B144;A55-B145; A55-B146; A55-B147; A55-B148; A55-B149; A55-B150; A55-B151;A55-B152; A55-B153; A55-B154; A55-B155; A55-B156; A55-B157; A55-B158;A55-B159; A55-B160; A55-B161; A55-B162; A55-B163; A55-B164; A55-B165;A55-B166; 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A75-B164; A75-B165; A75-B166; A75-B167; A75-B168;A75-B169; A76-B1; A76-B2; A76-B3; A76-B4; A76-B5; A76-B6; A76-B7;A76-B8; A76-B9; A76-B10; A76-B11; A76-B12; A76-B13; A76-B14; A76-B15;A76-B16; A76-B17; A76-B18; A76-B19; A76-B20; A76-B21; A76-B22; A76-B23;A76-B24; A76-B25; A76-B26; A76-B27; A76-B28; A76-B29; A76-B30; A76-B31;A76-B32; A76-B33; A76-B34; A76-B35; A76-B36; A76-B37; A76-B38; A76-B39;A76-B40; A76-B41; A76-B42; A76-B43; A76-B44; A76-B45; A76-B46; A76-B47;A76-B48; A76-B49; A76-B50; A76-B51; A76-B52; A76-B53; A76-B54; A76-B55;A76-B56; A76-B57; A76-B58; A76-B59; A76-B60; A76-B61; A76-B62; A76-B63;A76-B64; A76-B65; A76-B66; A76-B67; A76-B68; A76-B69; A76-B70; A76-B71;A76-B72; A76-B73; A76-B74; A76-B75; A76-B76; A76-B77; A76-B78; A76-B79;A76-B80; A76-B81; A76-B82; A76-B83; A76-B84; A76-B85; A76-B86; A76-B87;A76-B88; A76-B89; A76-B90; A76-B91; A76-B92; A76-B93; A76-B94; A76-B95;A76-B96; A76-B97; A76-B98; A76-B99; A76-B100; A76-B101; A76-B102;A76-B103; A76-B104; A76-B105; A76-B106; A76-B107; 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A79-B33; A79-B34; A79-B35; A79-B36; A79-B37; A79-B38; A79-B39;A79-B40; A79-B41; A79-B42; A79-B43; A79-B44; A79-B45; A79-B46; A79-B47;A79-B48; A79-B49; A79-B50; A79-B51; A79-B52; A79-B53; A79-B54; A79-B55;A79-B56; A79-B57; A79-B58; A79-B59; A79-B60; A79-B61; A79-B62; A79-B63;A79-B64; A79-B65; A79-B66; A79-B67; A79-B68; A79-B69; A79-B70; A79-B71;A79-B72; A79-B73; A79-B74; A79-B75; A79-B76; A79-B77; A79-B78; A79-B79;A79-B80; A79-B81; A79-B82; A79-B83; A79-B84; A79-B85; A79-B86; A79-B87;A79-B88; A79-B89; A79-B90; A79-B91; A79-B92; A79-B93; A79-B94; A79-B95;A79-B96; A79-B97; A79-B98; A79-B99; A79-B100; A79-B101; A79-B102;A79-B103; A79-B104; A79-B105; A79-B106; A79-B107; A79-B108; A79-B109;A79-B110; A79-B111; A79-B112; A79-B113; A79-B114; A79-B115; A79-B116;A79-B117; A79-B118; A79-B119; A79-B120; A79-B121; A79-B122; A79-B123;A79-B124; A79-B125; A79-B126; A79-B127; A79-B128; A79-B129; A79-B130;A79-B131; A79-B132; A79-B133; A79-B134; A79-B135; A79-B136; A79-B137;A79-B138; A79-B139; A79-B140; A79-B141; 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A100-B76; A100-B77;A100-B78; A100-B79; A100-B80; A100-B81; A100-B82; A100-B83; A100-B84;A100-B85; A100-B86; A100-B87; A100-B88; A100-B89; A100-B90; A100-B91;A100-B92; A100-B93; A100-B94; A100-B95; A100-B96; A100-B97; A100-B98;A100-B99; A100-B100; A100-B101; A100-B102; A100-B103; A100-B104;A100-B105; A100-B106; A100-B107; A100-B108; A100-B109; A100-B110;A100-B111; A100-B112; A100-B113; A100-B114; A100-B115; A100-B116;A100-B117; A100-B118; A100-B119; A100-B120; A100-B121; A100-B122;A100-B123; A100-B124; A100-B125; A100-B126; A100-B127; A100-B128;A100-B129; A100-B130; A100-B131; A100-B132; A100-B133; A100-B134;A100-B135; A100-B136; A100-B137; A100-B138; A100-B139; A100-B140;A100-B141; A100-B142; A100-B143; A100-B144; A100-B145; A100-B146;A100-B147; A100-B148; A100-B149; A100-B150; A100-B151; A100-B152;A100-B153; A100-B154; A100-B155; A100-B156; A100-B157; A100-B158;A100-B159; A100-B160; A100-B161; A100-B162; A100-B163; A100-B164;A100-B165; A100-B166; A100-B167; A100-B168; A100-B169; A101-B1; A101-B2;A101-B3; A101-B4; A101-B5; A101-B6; A101-B7; A101-B8; A101-B9; A101-B10;A101-B11; A101-B12; A101-B13; A101-B14; A101-B15; A101-B16; A101-B17;A101-B18; A101-B19; A101-B20; A101-B21; A101-B22; A101-B23; A101-B24;A101-B25; A101-B26; A101-B27; A101-B28; A101-B29; A101-B30; A101-B31;A101-B32; A101-B33; A101-B34; A101-B35; A101-B36; A101-B37; A101-B38;A101-B39; A101-B40; A101-B41; A101-B42; A101-B43; A101-B44; A101-B45;A101-B46; A101-B47; A101-B48; A101-B49; A101-B50; A101-B51; A101-B52;A101-B53; A101-B54; A101-B55; A101-B56; A101-B57; A101-B58; A101-B59;A101-B60; A101-B61; A101-B62; A101-B63; A101-B64; A101-B65; A101-B66;A101-B67; A101-B68; A101-B69; A101-B70; A101-B71; A101-B72; A101-B73;A101-B74; A101-B75; A101-B76; A101-B77; A101-B78; A101-B79; A101-B80;A101-B81; A101-B82; A101-B83; A101-B84; A101-B85; A101-B86; A101-B87;A101-B88; A101-B89; A101-B90; A101-B91; A101-B92; A101-B93; A101-B94;A101-B95; A101-B96; A101-B97; A101-B98; A101-B99; A101-B100; A101-B101;A101-B102; A101-B103; A101-B104; A101-B105; A101-B106; A101-B107;A101-B108; A101-B109; A101-B110; A101-B111; A101-B112; A101-B113;A101-B114; A101-B115; A101-B116; A101-B117; A101-B118; A101-B119;A101-B120; A101-B121; A101-B122; A101-B123; A101-B124; A101-B125;A101-B126; A101-B127; A101-B128; A101-B129; A101-B130; A101-B131;A101-B132; A101-B133; A101-B134; A101-B135; A101-B136; A101-B137;A101-B138; A101-B139; A101-B140; A101-B141; A101-B142; A101-B143;A101-B144; A101-B145; A101-B146; A101-B147; A101-B148; A101-B149;A101-B150; A101-B151; A101-B152; A101-B153; A101-B154; A101-B155;A101-B156; A101-B157; A101-B158; A101-B159; A101-B160; A101-B161;A101-B162; A101-B163; A101-B164; A101-B165; A101-B166; A101-B167;A101-B168; A101-B169; A102-B1; A102-B2; A102-B3; A102-B4; A102-B5;A102-B6; A102-B7; A102-B8; A102-B9; A102-B10; A102-B11; A102-B12;A102-B13; A102-B14; A102-B15; A102-B16; A102-B17; A102-B18; A102-B19;A102-B20; A102-B21; A102-B22; A102-B23; A102-B24; A102-B25; A102-B26;A102-B27; A102-B28; A102-B29; A102-B30; A102-B31; A102-B32; A102-B33;A102-B34; A102-B35; A102-B36; A102-B37; A102-B38; A102-B39; A102-B40;A102-B41; A102-B42; A102-B43; A102-B44; A102-B45; A102-B46; A102-B47;A102-B48; A102-B49; A102-B50; A102-B51; A102-B52; A102-B53; A102-B54;A102-B55; A102-B56; A102-B57; A102-B58; A102-B59; A102-B60; A102-B61;A102-B62; A102-B63; A102-B64; A102-B65; A102-B66; A102-B67; A102-B68;A102-B69; A102-B70; A102-B71; A102-B72; A102-B73; A102-B74; A102-B75;A102-B76; A102-B77; A102-B78; A102-B79; A102-B80; A102-B81; A102-B82;A102-B83; A102-B84; A102-B85; A102-B86; A102-B87; A102-B88; A102-B89;A102-B90; A102-B91; A102-B92; A102-B93; A102-B94; A102-B95; A102-B96;A102-B97; A102-B98; A102-B99; A102-B100; A102-B101; A102-B102;A102-B103; A102-B104; A102-B105; A102-B106; A102-B107; A102-B108;A102-B109; A102-B110; A102-B111; A102-B112; A102-B113; A102-B114;A102-B115; A102-B116; A102-B117; A102-B118; A102-B119; A102-B120;A102-B121; A102-B122; A102-B123; A102-B124; A102-B125; A102-B126;A102-B127; A102-B128; A102-B129; A102-B130; A102-B131; A102-B132;A102-B133; A102-B134; A102-B135; A102-B136; A102-B137; A102-B138;A102-B139; A102-B140; A102-B141; A102-B142; A102-B143; A102-B144;A102-B145; A102-B146; A102-B147; A102-B148; A102-B149; A102-B150;A102-B151; A102-B152; A102-B153; A102-B154; A102-B155; A102-B156;A102-B157; A102-B158; A102-B159; A102-B160; A102-B161; A102-B162;A102-B163; A102-B164; A102-B165; A102-B166; A102-B167; A102-B168;A102-B169; A103-B1; A103-B2; A103-B3; A103-B4; A103-B5; A103-B6;A103-B7; A103-B8; A103-B9; A103-B10; A103-B11; A103-B12; A103-B13;A103-B14; A103-B15; A103-B16; A103-B17; A103-B18; A103-B19; A103-B20;A103-B21; A103-B22; A103-B23; A103-B24; A103-B25; A103-B26; A103-B27;A103-B28; A103-B29; A103-B30; A103-B31; A103-B32; A103-B33; A103-B34;A103-B35; A103-B36; A103-B37; A103-B38; A103-B39; A103-B40; A103-B41;A103-B42; A103-B43; A103-B44; A103-B45; A103-B46; A103-B47; A103-B48;A103-B49; A103-B50; A103-B51; A103-B52; A103-B53; A103-B54; A103-B55;A103-B56; A103-B57; A103-B58; A103-B59; A103-B60; A103-B61; A103-B62;A103-B63; A103-B64; A103-B65; A103-B66; A103-B67; A103-B68; A103-B69;A103-B70; A103-B71; A103-B72; A103-B73; A103-B74; A103-B75; A103-B76;A103-B77; A103-B78; A103-B79; A103-B80; A103-B81; A103-B82; A103-B83;A103-B84; A103-B85; A103-B86; A103-B87; A103-B88; A103-B89; A103-B90;A103-B91; A103-B92; A103-B93; A103-B94; A103-B95; A103-B96; A103-B97;A103-B98; A103-B99; A103-B100; A103-B101; A103-B102; A103-B103;A103-B104; A103-B105; A103-B106; A103-B107; A103-B108; A103-B109;A103-B110; A103-B111; A103-B112; A103-B113; A103-B114; A103-B115;A103-B116; A103-B117; A103-B118; A103-B119; A103-B120; A103-B121;A103-B122; A103-B123; A103-B124; A103-B125; A103-B126; A103-B127;A103-B128; A103-B129; A103-B130; A103-B131; A103-B132; A103-B133;A103-B134; A103-B135; A103-B136; A103-B137; A103-B138; A103-B139;A103-B140; A103-B141; A103-B142; A103-B143; A103-B144; A103-B145;A103-B146; A103-B147; A103-B148; A103-B149; A103-B150; A103-B151;A103-B152; A103-B153; A103-B154; A103-B155; A103-B156; A103-B157;A103-B158; A103-B159; A103-B160; A103-B161; A103-B162; A103-B163;A103-B164; A103-B165; A103-B166; A103-B167; A103-B168; A103-B169;A104-B1; A104-B2; A104-B3; A104-B4; A104-B5; A104-B6; A104-B7; A104-B8;A104-B9; A104-B10; A104-B11; A104-B12; A104-B13; A104-B14; A104-B15;A104-B16; A104-B17; A104-B18; A104-B19; A104-B20; A104-B21; A104-B22;A104-B23; A104-B24; A104-B25; A104-B26; A104-B27; A104-B28; A104-B29;A104-B30; A104-B31; A104-B32; A104-B33; A104-B34; A104-B35; A104-B36;A104-B37; A104-B38; A104-B39; A104-B40; A104-B41; A104-B42; A104-B43;A104-B44; A104-B45; A104-B46; A104-B47; A104-B48; A104-B49; A104-B50;A104-B51; A104-B52; A104-B53; A104-B54; A104-B55; A104-B56; A104-B57;A104-B58; A104-B59; A104-B60; A104-B61; A104-B62; A104-B63; A104-B64;A104-B65; A104-B66; A104-B67; A104-B68; A104-B69; A104-B70; A104-B71;A104-B72; A104-B73; A104-B74; A104-B75; A104-B76; A104-B77; A104-B78;A104-B79; A104-B80; A104-B81; A104-B82; A104-B83; A104-B84; A104-B85;A104-B86; A104-B87; A104-B88; A104-B89; A104-B90; A104-B91; A104-B92;A104-B93; A104-B94; A104-B95; A104-B96; A104-B97; A104-B98; A104-B99;A104-B100; A104-B101; A104-B102; A104-B103; A104-B104; A104-B105;A104-B106; A104-B107; A104-B108; A104-B109; A104-B110; A104-B111;A104-B112; A104-B113; A104-B114; A104-B115; A104-B116; A104-B117;A104-B118; A104-B119; A104-B120; A104-B121; A104-B122; A104-B123;A104-B124; A104-B125; A104-B126; A104-B127; A104-B128; A104-B129;A104-B130; A104-B131; A104-B132; A104-B133; A104-B134; A104-B135;A104-B136; A104-B137; A104-B138; A104-B139; A104-B140; A104-B141;A104-B142; A104-B143; A104-B144; A104-B145; A104-B146; A104-B147;A104-B148; A104-B149; A104-B150; A104-B151; A104-B152; A104-B153;A104-B154; A104-B155; A104-B156; A104-B157; A104-B158; A104-B159;A104-B160; A104-B161; A104-B162; A104-B163; A104-B164; A104-B165;A104-B166; A104-B167; A104-B168; A104-B169; A105-B1; A105-B2; A105-B3;A105-B4; A105-B5; A105-B6; A105-B7; A105-B8; A105-B9; A105-B10;A105-B11; A105-B12; A105-B13; A105-B14; A105-B15; A105-B16; A105-B17;A105-B18; A105-B19; A105-B20; A105-B21; A105-B22; A105-B23; A105-B24;A105-B25; A105-B26; A105-B27; A105-B28; A105-B29; A105-B30; A105-B31;A105-B32; A105-B33; A105-B34; A105-B35; A105-B36; A105-B37; A105-B38;A105-B39; A105-B40; A105-B41; A105-B42; A105-B43; A105-B44; A105-B45;A105-B46; A105-B47; A105-B48; A105-B49; A105-B50; A105-B51; A105-B52;A105-B53; A105-B54; A105-B55; A105-B56; A105-B57; A105-B58; A105-B59;A105-B60; A105-B61; A105-B62; A105-B63; A105-B64; A105-B65; A105-B66;A105-B67; A105-B68; A105-B69; A105-B70; A105-B71; A105-B72; A105-B73;A105-B74; A105-B75; A105-B76; A105-B77; A105-B78; A105-B79; A105-B80;A105-B81; A105-B82; A105-B83; A105-B84; A105-B85; A105-B86; A105-B87;A105-B88; A105-B89; A105-B90; A105-B91; A105-B92; A105-B93; A105-B94;A105-B95; A105-B96; A105-B97; A105-B98; A105-B99; A105-B100; A105-B101;A105-B102; A105-B103; A105-B104; A105-B105; A105-B106; A105-B107;A105-B108; A105-B109; A105-B110; A105-B111; A105-B112; A105-B113;A105-B114; A105-B115; A105-B116; A105-B117; A105-B118; A105-B119;A105-B120; A105-B121; A105-B122; A105-B123; A105-B124; A105-B125;A105-B126; A105-B127; A105-B128; A105-B129; A105-B130; A105-B131;A105-B132; A105-B133; A105-B134; A105-B135; A105-B136; A105-B137;A105-B138; A105-B139; A105-B140; A105-B141; A105-B142; A105-B143;A105-B144; A105-B145; A105-B146; A105-B147; A105-B148; A105-B149;A105-B150; A105-B151; A105-B152; A105-B153; A105-B154; A105-B155;A105-B156; A105-B157; A105-B158; A105-B159; A105-B160; A105-B161;A105-B162; A105-B163; A105-B164; A105-B165; A105-B166; A105-B167;A105-B168; A105-B169; A106-B1; A106-B2; A106-B3; A106-B4; A106-B5;A106-B6; A106-B7; A106-B8; A106-B9; A106-B10; A106-B11; A106-B12;A106-B13; A106-B14; A106-B15; A106-B16; A106-B17; A106-B18; A106-B19;A106-B20; A106-B21; A106-B22; A106-B23; A106-B24; A106-B25; A106-B26;A106-B27; A106-B28; A106-B29; A106-B30; A106-B31; A106-B32; A106-B33;A106-B34; A106-B35; A106-B36; A106-B37; A106-B38; A106-B39; A106-B40;A106-B41; A106-B42; A106-B43; A106-B44; A106-B45; A106-B46; A106-B47;A106-B48; A106-B49; A106-B50; A106-B51; A106-B52; A106-B53; A106-B54;A106-B55; A106-B56; A106-B57; A106-B58; A106-B59; A106-B60; A106-B61;A106-B62; A106-B63; A106-B64; A106-B65; A106-B66; A106-B67; A106-B68;A106-B69; A106-B70; A106-B71; A106-B72; A106-B73; A106-B74; A106-B75;A106-B76; A106-B77; A106-B78; A106-B79; A106-B80; A106-B81; A106-B82;A106-B83; A106-B84; A106-B85; A106-B86; A106-B87; A106-B88; A106-B89;A106-B90; A106-B91; A106-B92; A106-B93; A106-B94; A106-B95; A106-B96;A106-B97; A106-B98; A106-B99; A106-B100; A106-B101; A106-B102;A106-B103; A106-B104; A106-B105; A106-B106; A106-B107; A106-B108;A106-B109; A106-B110; A106-B111; A106-B112; A106-B113; A106-B114;A106-B115; A106-B116; A106-B117; A106-B118; A106-B119; A106-B120;A106-B121; A106-B122; A106-B123; A106-B124; A106-B125; A106-B126;A106-B127; A106-B128; A106-B129; A106-B130; A106-B131; A106-B132;A106-B133; A106-B134; A106-B135; A106-B136; A106-B137; A106-B138;A106-B139; A106-B140; A106-B141; A106-B142; A106-B143; A106-B144;A106-B145; A106-B146; A106-B147; A106-B148; A106-B149; A106-B150;A106-B151; A106-B152; A106-B153; A106-B154; A106-B155; A106-B156;A106-B157; A106-B158; A106-B159; A106-B160; A106-B161; A106-B162;A106-B163; A106-B164; A106-B165; A106-B166; A106-B167; A106-B168;A106-B169; A107-B1; A107-B2; A107-B3; A107-B4; A107-B5; A107-B6;A107-B7; A107-B8; A107-B9; A107-B10; A107-B11; A107-B12; A107-B13;A107-B14; A107-B15; A107-B16; A107-B17; A107-B18; A107-B19; A107-B20;A107-B21; A107-B22; A107-B23; A107-B24; A107-B25; A107-B26; A107-B27;A107-B28; A107-B29; A107-B30; A107-B31; A107-B32; A107-B33; A107-B34;A107-B35; A107-B36; A107-B37; A107-B38; A107-B39; A107-B40; A107-B41;A107-B42; A107-B43; A107-B44; A107-B45; A107-B46; A107-B47; A107-B48;A107-B49; A107-B50; A107-B51; A107-B52; A107-B53; A107-B54; A107-B55;A107-B56; A107-B57; A107-B58; A107-B59; A107-B60; A107-B61; A107-B62;A107-B63; A107-B64; A107-B65; A107-B66; A107-B67; A107-B68; A107-B69;A107-B70; A107-B71; A107-B72; A107-B73; A107-B74; A107-B75; A107-B76;A107-B77; A107-B78; A107-B79; A107-B80; A107-B81; A107-B82; A107-B83;A107-B84; A107-B85; A107-B86; A107-B87; A107-B88; A107-B89; A107-B90;A107-B91; A107-B92; A107-B93; A107-B94; A107-B95; A107-B96; A107-B97;A107-B98; A107-B99; A107-B100; A107-B101; A107-B102; A107-B103;A107-B104; A107-B105; A107-B106; A107-B107; A107-B108; A107-B109;A107-B110; A107-B111; A107-B112; A107-B113; A107-B114; A107-B115;A107-B116; A107-B117; A107-B118; A107-B119; A107-B120; A107-B121;A107-B122; A107-B123; A107-B124; A107-B125; A107-B126; A107-B127;A107-B128; A107-B129; A107-B130; A107-B131; A107-B132; A107-B133;A107-B134; A107-B135; A107-B136; A107-B137; A107-B138; A107-B139;A107-B140; A107-B141; A107-B142; A107-B143; A107-B144; A107-B145;A107-B146; A107-B147; A107-B148; A107-B149; A107-B150; A107-B151;A107-B152; A107-B153; A107-B154; A107-B155; A107-B156; A107-B157;A107-B158; A107-B159; A107-B160; A107-B161; A107-B162; A107-B163;A107-B164; A107-B165; A107-B166; A107-B167; A107-B168; A107-B169;A108-B1; A108-B2; A108-B3; A108-B4; A108-B5; A108-B6; A108-B7; A108-B8;A108-B9; A108-B10; A108-B11; A108-B12; A108-B13; A108-B14; A108-B15;A108-B16; A108-B17; A108-B18; A108-B19; A108-B20; A108-B21; A108-B22;A108-B23; A108-B24; A108-B25; A108-B26; A108-B27; A108-B28; A108-B29;A108-B30; A108-B31; A108-B32; A108-B33; A108-B34; A108-B35; A108-B36;A108-B37; A108-B38; A108-B39; A108-B40; A108-B41; A108-B42; A108-B43;A108-B44; A108-B45; A108-B46; A108-B47; A108-B48; A108-B49; A108-B50;A108-B51; A108-B52; A108-B53; A108-B54; A108-B55; A108-B56; A108-B57;A108-B58; A108-B59; A108-B60; A108-B61; A108-B62; A108-B63; A108-B64;A108-B65; A108-B66; A108-B67; A108-B68; A108-B69; A108-B70; A108-B71;A108-B72; A108-B73; A108-B74; A108-B75; A108-B76; A108-B77; A108-B78;A108-B79; A108-B80; A108-B81; A108-B82; A108-B83; A108-B84; A108-B85;A108-B86; A108-B87; A108-B88; A108-B89; A108-B90; A108-B91; A108-B92;A108-B93; A108-B94; A108-B95; A108-B96; A108-B97; A108-B98; A108-B99;A108-B100; A108-B101; A108-B102; A108-B103; A108-B104; A108-B105;A108-B106; A108-B107; A108-B108; A108-B109; A108-B110; A108-B111;A108-B112; A108-B113; A108-B114; A108-B115; A108-B116; A108-B117;A108-B118; A108-B119; A108-B120; A108-B121; A108-B122; A108-B123;A108-B124; A108-B125; A108-B126; A108-B127; A108-B128; A108-B129;A108-B130; A108-B131; A108-B132; A108-B133; A108-B134; A108-B135;A108-B136; A108-B137; A108-B138; A108-B139; A108-B140; A108-B141;A108-B142; A108-B143; A108-B144; A108-B145; A108-B146; A108-B147;A108-B148; A108-B149; A108-B150; A108-B151; A108-B152; A108-B153;A108-B154; A108-B155; A108-B156; A108-B157; A108-B158; A108-B159;A108-B160; A108-B161; A108-B162; A108-B163; A108-B164; A108-B165;A108-B166; A108-B167; A108-B168; A108-B169; A109-B1; A109-B2; A109-B3;A109-B4; A109-B5; A109-B6; A109-B7; A109-B8; A109-B9; A109-B10;A109-B11; A109-B12; A109-B13; A109-B14; A109-B15; A109-B16; A109-B17;A109-B18; A109-B19; A109-B20; A109-B21; A109-B22; A109-B23; A109-B24;A109-B25; A109-B26; A109-B27; A109-B28; A109-B29; A109-B30; A109-B31;A109-B32; A109-B33; A109-B34; A109-B35; A109-B36; A109-B37; A109-B38;A109-B39; A109-B40; A109-B41; A109-B42; A109-B43; A109-B44; A109-B45;A109-B46; A109-B47; A109-B48; A109-B49; A109-B50; A109-B51; A109-B52;A109-B53; A109-B54; A109-B55; A109-B56; A109-B57; A109-B58; A109-B59;A109-B60; A109-B61; A109-B62; A109-B63; A109-B64; A109-B65; A109-B66;A109-B67; A109-B68; A109-B69; A109-B70; A109-B71; A109-B72; A109-B73;A109-B74; A109-B75; A109-B76; A109-B77; A109-B78; A109-B79; A109-B80;A109-B81; A109-B82; A109-B83; A109-B84; A109-B85; A109-B86; A109-B87;A109-B88; A109-B89; A109-B90; A109-B91; A109-B92; A109-B93; A109-B94;A109-B95; A109-B96; A109-B97; A109-B98; A109-B99; A109-B100; A109-B101;A109-B102; A109-B103; A109-B104; A109-B105; A109-B106; A109-B107;A109-B108; A109-B109; A109-B110; A109-B111; A109-B112; A109-B113;A109-B114; A109-B115; A109-B116; A109-B117; A109-B118; A109-B119;A109-B120; A109-B121; A109-B122; A109-B123; A109-B124; A109-B125;A109-B126; A109-B127; A109-B128; A109-B129; A109-B130; A109-B131;A109-B132; A109-B133; A109-B134; A109-B135; A109-B136; A109-B137;A109-B138; A109-B139; A109-B140; A109-B141; A109-B142; A109-B143;A109-B144; A109-B145; A109-B146; A109-B147; A109-B148; A109-B149;A109-B150; A109-B151; A109-B152; A109-B153; A109-B154; A109-B155;A109-B156; A109-B157; A109-B158; A109-B159; A109-B160; A109-B161;A109-B162; A109-B163; A109-B164; A109-B165; A109-B166; A109-B167;A109-B168; A109-B169; A110-B1; A110-B2; A110-B3; A110-B4; A110-B5;A110-B6; A110-B7; A110-B8; A110-B9; A110-B10; A110-B11; A110-B12;A110-B13; A110-B14; A110-B15; A110-B16; A110-B17; A110-B18; A110-B19;A110-B20; A110-B21; A110-B22; A110-B23; A110-B24; A110-B25; A110-B26;A110-B27; A110-B28; A110-B29; A110-B30; A110-B31; A110-B32; A110-B33;A110-B34; A110-B35; A110-B36; A110-B37; A110-B38; A110-B39; A110-B40;A110-B41; A110-B42; A110-B43; A110-B44; A110-B45; A110-B46; A110-B47;A110-B48; A110-B49; A110-B50; A110-B51; A110-B52; A110-B53; A110-B54;A110-B55; A110-B56; A110-B57; A110-B58; A110-B59; A110-B60; A110-B61;A110-B62; A110-B63; A110-B64; A110-B65; A110-B66; A110-B67; A110-B68;A110-B69; A110-B70; A110-B71; A110-B72; A110-B73; A110-B74; A110-B75;A110-B76; A110-B77; A110-B78; A110-B79; A110-B80; A110-B81; A110-B82;A110-B83; A110-B84; A110-B85; A110-B86; A110-B87; A110-B88; A110-B89;A110-B90; A110-B91; A110-B92; A110-B93; A110-B94; A110-B95; A110-B96;A110-B97; A110-B98; A110-B99; A110-B100; A110-B101; A110-B102;A110-B103; A110-B104; A110-B105; A110-B106; A110-B107; A110-B108;A110-B109; A110-B110; A110-B111; A110-B112; A110-B113; A110-B114;A110-B115; A110-B116; A110-B117; A110-B118; A110-B119; A110-B120;A110-B121; A110-B122; A110-B123; A110-B124; A110-B125; A110-B126;A110-B127; A110-B128; A110-B129; A110-B130; A110-B131; A110-B132;A110-B133; A110-B134; A110-B135; A110-B136; A110-B137; A110-B138;A110-B139; A110-B140; A110-B141; A110-B142; A110-B143; A110-B144;A110-B145; A110-B146; A110-B147; A110-B148; A110-B149; A110-B150;A110-B151; A110-B152; A110-B153; A110-B154; A110-B155; A110-B156;A110-B157; A110-B158; A110-B159; A110-B160; A110-B161; A110-B162;A110-B163; A110-B164; A110-B165; A110-B166; A110-B167; A110-B168;A110-B169.

Thus, for example, in the above list the compound denoted as A9-B9 isthe product of the combination of group A9 in Table 1 and B9 in Table 2,namely

Example 230(a) hereinafter described.

Particular compounds of the invention of formula (Ix) for the inhibitionof SYK are:

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-methylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-isopropylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenethylamide;-   5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole;-   2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   5,6-dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   5-fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5,6-dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole    hydrochloride;-   5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(5-(4-methoxy-benzylsulfanyl)₄-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole;-   2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    methyl ester;-   3-(1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone;-   2-(1H-indazol-3-yl)-3H-benzoimidazol-4-ol;-   2-phenyl-1H-imidazol[4,5-b]pyrazine;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine;-   2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine;-   2-(1H-pyrazol-3-yl)-1H-benzoimidazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole;-   5,6-dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(2-methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(4-chloro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(4-methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile;-   3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid    ethyl ester;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylic    acid ethyl ester;-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-methoxy-ethyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    propylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (tetrahydro-pyran-4-yl)-amide;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile;-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile;-   2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(5-methylsulfanyl-isoxazol-3-yl)-1H-benzoimidazole;-   5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5,6-dichloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   (benzoimidazol-2-yl)-5-methylthio-3-pyrazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole;-   2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   2-(5-ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole;-   4-chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol;-   3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide;-   3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    methylamide;-   [2-indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    dimethylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    isopropylamide;-   1H-benzoimidazol-5-yl]-carboxylic acid, benzylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-hydroxy-1,1-dimethylethyl)-amide;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid (pyridin-3-ylmethyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid phenylmethyl-amide;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid (pyridin-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-morpholin-4-yl-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-methoxy-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-cyano-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-imidazol-1-yl-propyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isobutyl-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl-1H-pyrazole-4-carboxylic acid    cyclopropylmethyl-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid tert-butylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid    dimethylamide;-   2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid benzylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid;-   3-(5,6-dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylic    acid;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide;-   cyclopropanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   methoxyacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopentanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   trimethylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   tert-butylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   butanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   isoxazole-5-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   S(+)-2-methylbutanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic    acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea;-   cyclopropanecarboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide;-   cyclopropanecarboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3,5-dimethyl-isoxazole-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   furan-3-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]4-methyl-benzamide;-   5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5-ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5-fluoro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(4-nitro-1H-pyrazol-3-yl)-5-trifluoromethoxy-1H-benzoimidazole;-   2-(4-nitro-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole;-   5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide;-   cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone;-   isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid tert-butyl ester;-   5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid tert-butyl ester;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid tert-butyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid tert-butyl ester;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide;-   2-dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2{RH-1,2,3,4-tetraazol-1-yl)-acetamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide;-   2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea;-   1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide;-   cyclopropanecarboxylic    acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine;-   4-methylpiperazine-1-carboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide;-   1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea;-   cyclopropanecarboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   tetrahydropyran-4-carboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide;-   morpholine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   piperidine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea;-   5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole;-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide;-   3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea;-   piperidine-1-carboxylic acid    [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide;-   morpholine-4-carboxylic    acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   piperidine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   morpholine-4-carboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpbolin-4-yl-methanone;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [2-(2H-tetrazol-5-yl)ethyl]-amide;-   1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   morpholine-4-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea;-   1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic    acid amide dihydrochloride;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic    acid;-   2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid;-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-piperidin-1-yl-ethyl)-amide;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-2-ylmethyl)-amide;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(4-methyl-piperazin-1-yl)-propyl]-amide;-   N-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide;-   N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine;-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixa) of the invention for the inhibitionof SYK are:—

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-methylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-isopropylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenethylamide;-   5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole;-   2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   5,6-dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   5-fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5,6-dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole;-   2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole    hydrochloride;-   5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   2-(5-4-methoxy-benzylsulfanyl)-4-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole;-   2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole;-   3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine;-   5,6-dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole;-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-methoxy-ethyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    propylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (tetrahydro-pyran-4-yl)-amide;-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide;-   2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole;-   (benzoimidazol-2-yl)-5-methylthio-3-pyrazole;-   2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   2-(5-ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-hydroxy-1,1-dimethylethyl)-amide;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid (pyridin-3-ylmethyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid cyclopropylamide;-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid phenylmethyl-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isobutyl-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    cyclopropylmethyl-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid tert-butylamide;-   2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid benzylamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide;-   cyclopropanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   methoxyacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopentanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   trimethylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   tert-butylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   butanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   isoxazole-5-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   S(+)-2-methylbutanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic    acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea;-   cyclopropanecarboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide;-   cyclopropanecarboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3,5-dimethyl-isoxazole-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   furan-3-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]4-methyl-benzamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide;-   2-dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide;-   2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea;-   1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   cyclopropanecarboxylic    acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   4-methylpiperazine-1-carboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide;-   1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea;-   cyclopropanecarboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   tetrahydropyran-4-carboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide;-   morpholine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   piperidine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide;-   3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea;-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide;-   3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea;-   piperidine-1-carboxylic acid    [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   cyclopropanecarboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide;-   morpholine-4-carboxylic    acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   piperidine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   morpholine-4-carboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   piperidine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   morpholine-4-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea;-   4-methyl-piperazine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide;-   1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl-1H-pyrazol-4-yl]-3-isobutyl-urea;-   1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea;-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-piperidin-1-yl-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-2-ylmethyl)-amide;-   N-[2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-morpholinoamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(N′-methylpiperazino)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-pyrrolidinoamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(isobutyl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(cyclohexylmethyl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(2-furfuryl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-benzyl-N-methylamide;-   methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate;-   5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole;-   2-(1H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid;-   2-(5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid;-   5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole;-   5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole;-   2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole-   2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixa) of the invention forthe inhibition of SYK are:—

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide,    Example 1;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-methylamide, Example 2;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide,    Example 3;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-isopropylamide, Example 4;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenylamide, Example 5;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenethylamide, Example 6-   5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole,    (compound denoted as A9-B9), Example 230(a);-   6-chloro-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole,    (compound denoted as A12-B9), Example 230(b);-   6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole,    (compound denoted as A12-B10), Example 230(c);-   2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole,    (compound denoted as A4-B9), Example 230(d);-   2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole,    (compound denoted as A9-B11), Example 230(e);-   2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole,    (compound denoted as A9-B10), Example 230(f);-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide, Example 235(ab);-   3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(ai);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-methoxy-ethyl)-amide, Example 235(ak);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    propylamide, Example 235(al);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (tetrahydro-pyran-4-yl)-amide, Example 235(am);-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(ao);-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide, Example 235(ap);-   3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(aq);-   2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole,    (compound denoted as A9-B83), Example 241 (b);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide, (compound denoted as A9-B106), Example 246(g);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-hydroxy-1,1-dimethylethyl)-amide, (compound denoted as A9-B25),    Example 246(h);-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid (pyridin-3-ylmethyl)-amide, (compound denoted as A40-B106),    Example 246(i);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid cyclopropylamide, (compound denoted as A9-B105), Example    246(j);-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid phenylmethyl-amide, (compound denoted as A17-B106), Example    246(k);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isobutyl-amide, Example 246(v);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide, Example 246(w);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    cyclopropylmethyl-amide, Example 246(x);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid tert-butylamide, Example 246(y);-   2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid benzylamide, Example 246(aa);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide,    (compound denoted as A9-B85), Example 248(a);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide,    (compound denoted as A9-B86), Example 248(b);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide,    (compound denoted as A9-B36), Example 248(c);-   cyclopropanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,-   (compound denoted as A9-B89), Example 248(d);-   methoxyacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B94), Example 248(e);-   cyclopentanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B87), Example 248(f);-   trimethylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B88), Example 248(g);-   tert-butylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B90), Example 248(h);-   butanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B91), Example 248(i);-   isoxazole-5-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B96), Example 248(j);-   S(+)-2-methylbutanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B93), Example 248(k);-   cyclopropanecarboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A55-B89), Example 248(l);-   piperidine-1-carboxylic    acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(m);-   3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea,    Example 248(n);-   cyclopropanecarboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    248(o);-   cyclopropanecarboxylic acid    [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    248(p);-   cyclopropanecarboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(q);-   cyclopropanecarboxylic acid    [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(r);-   cyclopropanecarboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(s);-   N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide,    Example 248(t);-   cyclopropanecarboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(u);-   3,5-dimethyl-isoxazole-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(v);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide,    Example 248(w);-   furan-3-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(x);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide,    Example 248(y);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide,    (compound denoted as A9-B99), Example 253;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide,    (compound denoted as A9-B97), Example 254(a);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide;    Example 254(b);-   2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;    Example 254(c);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    (compound denoted as A9-B38), Example 255(a);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea,    (compound denoted as A9-B103), Example 255(b);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea,    (compound denoted as A9-B40), Example 255(c);-   1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    (compound denoted as A9-B39), Example 255(d);-   cyclopropanecarboxylic    acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 256(a);-   4-methylpiperazine-1-carboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide,    Example 256(c);-   1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea,    Example 256(d);-   cyclopropanecarboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(a);-   tetrahydropyran-4-carboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide,    Example 257(b);-   morpholine-4-arboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(c);-   piperidine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(d);-   3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea,    Example 257(e);-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide,    Example 257(g);-   3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 257(h);-   piperidine-1-carboxylic acid    [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 257(i);-   cyclopropanecarboxylic acid    [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(a);-   cyclopropanecarboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide,    Example 258(b);-   morpholine-4-carboxylic    acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(c);-   piperidine-1-carboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    258(d);-   3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(e);-   piperidine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(f);-   3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(g);-   morpholine-4-carboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(h);-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(n);-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(o);-   1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(a);-   1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(b);-   4-methyl-piperazine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(c);-   piperidine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(d);-   1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(e);-   morpholine-4-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(f);-   4-methyl-piperazine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(g);-   1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(h);-   1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(i);-   4-methyl-piperazine-1-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(j);-   1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(k);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea,    Example 260(l);-   4-methyl-piperazine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(m);-   1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(n);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 260(o);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea,    Example 260(p);-   1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(q);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(r);-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-piperidin-1-yl-ethyl)-amide, Example 246(ab);-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-2-ylmethyl)-amide, Example 246(ac);-   N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide,    Example 253(c);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixa), denoted as the productof the combination of group A1 in Table I and B1 in Table 2, of theinvention for the inhibition of SYK are:—

-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide, Example 235(ah);-   3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(ai);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-methoxy-ethyl)-amide, Example 235(ak);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    propylamide, Example 235(al);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (tetrahydro-pyran-4-yl)-amide, Example 235(am);-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(ao);-   3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide, Example 235(ap);-   3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(aq);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide, (compound denoted as A9-B106), Example 246(g);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (2-hydroxy-1,1-dimethyl-ethyl)-amide, (compound denoted as A9-B25),    Example 246(h);-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid (pyridin-3-ylmethyl)-amide, (compound denoted as A40-B106),    Example 246(i);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid cyclopropylamide, (compound denoted as A9-B105), Example    246(j);-   2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid phenylmethyl-amide, (compound denoted as A17-B106), Example    246(k);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isobutyl-amide, Example 246(v);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isopropylamide, Example 246(w);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    cyclopropylmethyl-amide, Example 246(x);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid tert-butylamide, Example 246(y);-   2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic    acid benzylamide, Example 246(aa);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide,    (compound denoted as A9-B85), Example 248(a);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide,    (compound denoted as A9-B86), Example 248(b);-   cyclopropanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B89), Example 248(d);-   methoxyacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B94), Example 248(e);-   cyclopentanecarboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B87), Example 248(f);-   trimethylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B88), Example 248(g);-   tert-butylacetic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B90), Example 248(h);-   butanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B91), Example 248(i);-   isoxazole-5-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B96), Example 248(j);-   S(+)-2-methylbutanoic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A9-B93), Example 248(k);-   cyclopropanecarboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    (compound denoted as A55-B89), Example 248(l);-   piperidine-1-carboxylic    acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(m);-   3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea,    Example 248(n);-   cyclopropanecarboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    248(o);-   cyclopropanecarboxylic acid    [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    248(p);-   cyclopropanecarboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(q);-   cyclopropanecarboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(s);-   N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide,    Example 248(t);-   cyclopropanecarboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(u);-   3,5-dimethyl-isoxazole-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(v);-   furan-3-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 248(x);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide,    (compound denoted as A9-B99), Example 253;-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide,    (compound denoted as A9-B97), Example 254(a);-   N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide;    Example 254(b);-   2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide;    Example 254(c);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    (compound denoted as A9-B38), Example 255(a);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea,    (compound denoted as A9-B103), Example 255(b);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea,    (compound denoted as A9-B40), Example 255(c);-   1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    (compound denoted as A9-B39), Example 255(d);-   cyclopropanecarboxylic    acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 256(a);-   4-methylpiperazine-1-carboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide,    Example 256(c);-   1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea,    Example 256(d);-   cyclopropanecarboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(a);-   tetrahydropyran-4-carboxylic acid    [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide,    Example 257(b);-   morpholine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(c);-   piperidine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(d);-   3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea,    Example 257(e);-   3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 257(h);-   piperidine-1-carboxylic acid    [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 257(i);-   cyclopropanecarboxylic acid    [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(a);-   cyclopropanecarboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide,    Example 258(b);-   morpholine-4-carboxylic    acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(c);-   piperidine-1-carboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    258(d);-   3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(e);-   piperidine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(f);-   3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(g);-   morpholine-4-carboxylic acid    [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(h);-   morpholine-4-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(n);-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(o);-   1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(a);-   1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(b);-   4-methyl-piperazine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(c);-   piperidine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(d);-   1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(e);-   morpholine-4-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(f);-   1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(h);-   1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea,    Example 260(i);-   4-methyl-piperazine-1-carboxylic acid    [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(j);-   1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(k);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea,    Example 260(l);-   4-methyl-piperazine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(m);-   1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(n);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 260(o);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea,    Example 260(p);-   1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(q);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    (compound denoted as A9-B142), Example 258(r);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

More especially preferred compounds of formula (Ixa) of the inventionfor the inhibition of SYK are:—

-   3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic    acid isopropylamide, Example 235(ai);-   3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic    acid cyclopropylamide, Example 235(ah);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    (tetrahydro-pyran-4-yl)-amide, Example 235(am);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid    isobutyl-amide, Example 246(v);-   cyclopropanecarboxylic    acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 256(a);-   1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea,    Example 256(d);-   piperidine-4-carboxylic    acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide,    Example 257(d);-   3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea,    Example 257(e);-   3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 257(h);-   piperidine-1-carboxylic acid    [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 257(i);-   cyclopropanecarboxylic acid    [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide,    Example 258(b);-   piperidine-1-carboxylic acid    [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide, Example    258(d);-   piperidine-1-carboxylic acid    [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(f);-   piperidine-1-carboxylic acid    [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 258(o);-   1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(a);-   piperidine-1-carboxylic acid    [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide,    Example 260(d);-   1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(k);-   1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(n);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea,    Example 260(o);-   1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea,    Example 260(q);-   3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea,    Example 258(r);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixb) of the invention for the inhibitionof SYK are:—

-   3-(1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone;-   2-(1H-indazol-3-yl)-3H-benzoimidazol-4-ol;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine;-   2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole;-   3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-bromo-1H-benzoimidazol-2-yl 1H-indazole;-   3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(2-methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(4-chloro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-(4-methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile;-   3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole;-   3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide;-   3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    methylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    dimethylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    isopropylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    benzylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-morpholin-4-yl-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-methoxy-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-cyano-ethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-hydroxy-1,1-dimethyl-ethyl)-amide;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-imidazol-1-yl-propyl)-amide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid    dimethylamide;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid;-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic    acid amide dihydrochloride;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixb), denoted as theproduct of the combination of group A1 in Table 1 and B1 in Table 2, ofthe invention for the inhibition of SYK are:—

-   3-(1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as A1-B63),    Example 234(a);-   3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted    as A6-B63), Example 234(b);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A9-B63), Example 234(f);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole,    (compound denoted as A9-B68), Example 235(b);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole,    (compound denoted as A9-B70), Example 235(d);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole,    (compound denoted as A9-B71), Example 235(e);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole,    (compound denoted as A9-B64), Example 235(f);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole,    (compound denoted as A9-B69), Example 235(g);-   3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as    A27-B63), Example 235(i);-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A55-B63), Example 235(j);-   3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole,    (compound denoted as A54-B63), Example 235(k);-   3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A58-B63), Example 235(l);-   3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as    A32-B63), Example 235(m);-   3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A68-B63), Example 235(n);-   3-(5-(pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A69-B63), Example 235(o);-   3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A57-B63), Example 235(p);-   3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as    A60-B63), Example 235(q);-   3-(5-2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A65-B63), Example 235(r);-   3-(5-(3,4-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole,    (compound denoted as A66-B63), Example 235(s);-   3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted    as A74-B63), Example 235(w);-   3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A22-B63), Example 235(x);-   3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A23-B63), Example 235(y);-   3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted    as A56-B63), Example 235(z);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile, (compound    denoted as A33-B63), Example 235(ab);-   3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A35-B63), Example 235(ac);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole,    (compound denoted as A9-B63), (compound denoted as A9-B112), Example    235(ad);-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole,    Example 235(aj);-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile,    Example 235(an);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile,    Example 235(ar);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)₄-fluoro-1H-indazole,    (compound denoted as A9-B110), Example 242(a);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole,    (compound denoted as A9-B109), Example 242(c);-   3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted    as A28-B63), Example 244(a);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide,    Example 244(b);-   3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole; Example    244(c)-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol, (compound    denoted as A34-B63), Example 245;-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    ethylamide, (compound denoted as A36-B63), Example 246(a);-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    methylamide, (compound denoted as A15-B63), Example 246(b);-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    isopropylamide, (compound denoted as A16-B63), Example 246(d);-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,    benzylamide, (compound denoted as A17-B63), Example 246(e);-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide,    (compound denoted as A52-B63), Example 246(f);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-3-ylmethyl)-amide, Example 246(m);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide, Example 246(n);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methyl-benzylamide, Example 246(o);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide, Example 246(p);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-morpholin-4-yl-ethyl)-amide, Example 246(q);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-methoxy-ethyl)-amide, Example 246(r);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-cyano-ethyl)-amide, Example 246(s);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-hydroxy-1,1-dimethyl-ethyl)-amide, Example 246(t);-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-imidazol-1-yl-propyl)-amide, Example 246(u),-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid    dimethylamide, Example 246(x);-   [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, (compound    denoted as A14-B63), Example 247(a);-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic    acid amide dihydrochloride, Example 262;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixb) of the invention for theinhibition of SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole,    (compound denoted as A9-B68), Example 235(b);-   3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound    denoted as A55-B63), Example 235(j);-   3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted    as A56-B63), Example 235(z);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid    dimethylamide, Example 246(x);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixc) of the invention for the inhibitionof SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole;    5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixc), denoted as theproduct of the combination of group A1 in Table 1 and B1 in Table 2, ofthe invention for the inhibition of SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole,    (compound denoted as A9-B59), Example 241(a);-   5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole,    (compound denoted as A9-B56), Example 241(d);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixd) of the invention for the inhibitionof SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide;-   cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone;-   isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid dimethylamide;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3-methyl-butan-1-one;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixd), denoted as theproduct of the combination of group A1 in Table 1 and B1 in Table 2, ofthe invention for the inhibition of SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide, (compound denoted as A9-B121), Example 250(a);-   cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone,    (compound denoted as A9-B122);-   isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone;-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid methyl ester;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide; 26(e)-   prepared    3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone;-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone;-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide;-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid dimethylamide, (compound denoted as A9-B119);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one,    (compound denoted as A9-B117);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid methyl ester, (compound denoted as A9-B120);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3-methyl-butan-1-one,    (compound denoted as A9-B118);-   1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one,    (compound denoted as A9-B123);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Especially preferred compounds of formula (Ixd), denoted as the productof the combination of group A1 in Table 1 and B1 in Table 2, of theinvention for the inhibition of SYK are:—

-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide, (compound denoted as A9-B121), Example 250(a);-   cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone,    (compound denoted as A9-B122); Example 250(b);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid isopropylamide, Example 255(e);-   prepared    3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid diethylamide, Example 258(i);-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone,    Example 258(j);-   [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone,    Example 258(k);-   3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-e]pyridine-5-carboxylic    acid diethylamide, Example 258(m);-   3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic    acid dimethylamide, (compound denoted as A9-B119);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particular compounds of formula (Lx) of the invention for the inhibitionof KDR are:—

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-methylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-isopropylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenethylamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-morpholinoamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(N′-methylpiperazino)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-pyrrolidinoamide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(isobutyl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(cyclohexylmethyl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(2-furfuryl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-benzyl-N-methylamide;-   methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate;-   5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole;-   5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole;-   2-(1H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid;-   5-bromo 2-(1H-indazol-3-yl)-3H-benzimidazole;-   2-(5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid;-   5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole;-   5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole;-   2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole;-   2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole.-   2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-ethoxy-propyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methanesulfonyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (naphthalen-1-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-dimethylamino-benzylamide;-   4-({[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic    acid tert-butyl ester;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-bromo-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[1,3]dioxol-5-ylmethyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;-   2(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-trifluoromethoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-methyl-thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-phenoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-trifluoromethoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-isopropoxy-propyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1-methyl-1H-pyrazol-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-isopropyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,5-dimethyl-furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(3-acetylamino-phenoxy)-propyl]-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-chloro-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    ([2,2′]bithiophenyl-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-cyano-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (5-chloro-benzo[b]thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (tetrahydro-pyran-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,5-dimethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1-methyl-1H-benzoimidazol-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-chloro-benzylamide;-   2-(1H-indazol-3-yl)₃H-benzoimidazole-4-carboxylic acid    4-sulfamoyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (3-ethoxy-propyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    4-bromo-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (naphthalen-1-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    4-dimethylamino-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    4-nitro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-bromo-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-methoxy-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    4-phenoxy-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-trifluoromethoxy-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (6-chloro-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (2,3-dihydro-benzofuran-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    2-nitro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3,5-dimethyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-chloro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    phenethyl-amide;-   3-(6-phenyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(2,4-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-naphthalen-1-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3,5-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-thianthren-1-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-biphenyl-4-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-p-tolyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-m-tolyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-m-tolyl-1H-benzoimidazol-2-yl}2H-indazole;-   3-(6-thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3,5-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3,4-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-benzo[1,3]dioxol-5-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(4-tert-butyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-hex-1-enyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3,4-dimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol;-   4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol;-   3-[6-(3,4-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   1-{4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-ethanone;-   3-(6-benzo[b]thiophen-2-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3,4,5-trimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   1-{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}-ethanone;-   1-{3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-ethanone;-   3-[6-(4-benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(2-fluoro-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-benzo[b]thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   {3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol;-   3-[6-(4-ethylsulfanyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(2,4-difluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-fluoro-2-methyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-{6-[2-(4-fluoro-phenyl)-vinyl]-1H-benzoimidazol-2-yl}-2H-indazole;-   3-{6-[2-(4-chloro-phenyl)-vinyl]-1H-benzoimidazol-2-yl}-2H-indazole;-   3-{4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-propionic    acid;-   {4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol;-   3-(6-furan-2-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3-benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-isopropyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-methanesulfonyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (tetrahydro-pyran-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-acetylamino-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    isopropylamide;-   [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-methanone;-   [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    benzyl-methyl-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,6-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,4-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,4,5-trifluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (4′-chloro-biphenyl-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3′,5′-dichloro-biphenyl-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (4′-fluoro-biphenyl-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,6-difluoro-3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2′-chloro-biphenyl-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-trifluoromethyl-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-imidazol-1-yl-propyl)-amide;-   4-[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,6-difluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,4-dichloro-6-fluoro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-fluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-fluoro-4-chloro-6-methyl-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-methoxy-pyridin-3-ylmethyl)-amide;-   2-[5-(benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-phenyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(2-methyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3,7-dimethyl-octa-2,6-dienyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-bromo-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   3-[5-(1H-benzoimidazol-2-yl]-1H-pyrazol-3-yloxymethyl]-benzonitrile;-   2-[5-(4-trifluoromethyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-pentafluorophenylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(4-tert-butyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(2-benzenesulfonylmethyl-benzyloxy)-2H-pyrazol-3-y]-1H-benzoimidazole;-   4-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxymethyl]-benzonitrile;-   2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2,3-dichloro-benzenesulfonic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   2-[5-(2-morpholin-4-yl-ethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(2-piperidin-1-yl-ethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-methoxy-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-p-tolyl-ethanone;-   1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-3,3,4,4,4-pentafluoro-butan-2-one;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-biphenyl-4-yl-ethanone;-   1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-butan-2-one;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-dimethylamino-phenyl)-ethanone;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(3-phenyl-isoxazol-5-yl)-ethanone;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-N-phenyl-acetamide;-   1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-3,3-dimethyl-butan-2-one;-   1-adamantan-1-yl-2-[5-(1H-benzoimidazol-2-yl    1H-pyrazol-3-yloxy]-ethanone;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-naphthalen-2-yl-ethanone;-   4-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-benzonitrile;-   6-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-3,4-dihydro    1H-quinolin-2-one;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-trifluoromethoxy-phenyl)-ethanone;-   5-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-2-chloro-benzenesulfonamide;-   2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-methoxy-phenyl)-ethanone;-   2-[5    (1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-cyclopropyl-ethanone;-   isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   2,2-dimethyl-propionic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   benzyloxy-acetic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl    ester,-   benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   4-methoxy-benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl    ester,-   phenyl-acetic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   2,3,4,5,6-Pentafluoro-benzoic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   cyclopropanecarboxylic acid 5-(1H-benzoimidazol-2-yl 1H-pyrazol-3-yl    ester;-   2,2,3,3,4,4,4-heptafluoro-butyric acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   cyclopentanecarboxylic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   3-phenyl-propionic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl    ester,-   biphenyl-4-carboxylic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl    ester;-   3,5-bis-trifluoromethyl-benzoic acid    5-(H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   4-trifluoromethyl-benzoic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   thiophene-2-carboxylic acid    5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixa), denoted as the product of thecombination of group A1 in Table 1 and B1 in Table 2, of the inventionfor the inhibition of KDR are:—

-   2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole, (compound    denoted as A9-B3);-   2-(5-methyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole (compound    denoted as A9-B2);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Preferred compounds of formula (Ixb), denoted as the product of thecombination of group A1 in Table 1 and B1 in Table 2, of the inventionfor the inhibition of KDR are:—

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide,    (compound denoted as A17-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-methylamide, (compound denoted as A15-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide,    (compound denoted as A36-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-isopropylamide, (compound denoted as A37-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenylamide, (compound denoted as A52-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-phenethylamide, (compound denoted as A51-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-morpholinoamide, (compound denoted as A92-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(N′-methylpiperazino)amide, (compound denoted as A93-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-pyrrolidinoamide, (compound denoted as A91-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(isobutyl)amide, (compound denoted as A82-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(cyclohexylmethyl)amide, (compound denoted as A83-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(2-furfuryl)amide, (compound denoted as A84-B63);-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-benzyl-N-methylamide, (compound denoted as A90-B63);-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-ethoxy-propyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methanesulfonyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (naphthalen-1-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-dimethylamino-benzylamide;-   4-({[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic    acid tert-butyl ester;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-bromo-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[1,3]dioxol-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-trifluoromethoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-methyl-thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-trifluoromethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-phenoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-trifluoromethoxy-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-isopropoxy-propyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1-methyl-1H-pyrazol-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-isopropyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,5-dimethyl-furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(3-acetylamino-phenoxy)-propyl]-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-chloro-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    ([2,2′]bithiophenyl-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-cyano-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (tetrahydro-pyran-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (thiophen-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,5-dimethyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (1-methyl-1H-benzoimidazol-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-chloro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    4-sulfamoyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3-methoxy-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    (furan-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    2-nitro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    3,5-dimethyl-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenylamide;-   3-[6-(4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-m-tolyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-o-tolyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(3,5-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-(6-benzo[1,3]dioxol-5-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-(6-hex-1-enyl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(3,4-dimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol;-   4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol;-   3-[6-(3,4,5-trimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   1-{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}-ethanone;-   {3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol;-   3-[6-(2,4-difluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   3-[6-(4-fluoro-2-methyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   {4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol;-   3-(6-furan-2-yl-1H-benzoimidazol-2-yl)-2H-indazole;-   3-[6-(4-isopropyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (tetrahydro-pyran-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-acetylamino-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    isopropylamide;-   [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-methanone;-   [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    benzyl-methyl-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,6-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,4-difluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3,4,5-trifluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,6-difluoro-3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2′-chloro-biphenyl-4-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-trifluoromethyl-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-imidazol-1-yl-propyl)-amide;-   4-[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-piperazine-1-carboxylic    acid tert-butyl ester;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,6-difluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,4-dichloro-6-fluoro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-fluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-fluoro-4-chloro-6-methyl-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-methoxy-pyridin-3-ylmethyl)-amide;-   2-[5-(benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-phenyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3,7-dimethyl-octa-2,6-dienyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-bromo-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(2-benzenesulfonylmethyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   2-[5-(3-methoxy-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole;-   isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester;-   3-phenyl-propionic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl    ester,-   methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate;-   5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole;-   5-bromo 2-(1H-indazol-3-yl)-3H-benzimidazole, (compound denoted as    A32-B63);-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particularly preferred compounds of formula (Ixb) of the invention forthe inhibition of KDR are:—

-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-cyclohexylmethyl)amide;-   2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid    N-(2-furfuryl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-methanesulfonyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-nitro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-chloro-pyridin-3-ylmethyl)-amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-ylmethyl)-amide;-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (benzo[b]thiophen-3-ylmethyl)-amide;    2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    3-chloro-benzylamide;-   2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid    2-methylsulfanyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-bromo-2-fluoro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    2,4-dichloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    4-chloro-2-methyl-benzylamide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,6-difluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2,4-dichloro-6-fluoro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (3-fluoro-4-chloro-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-fluoro-4-chloro-6-methyl-benzyl)amide;-   2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (6-methoxy-pyridin-3-ylmethyl)-amide;-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

Particular compounds of formula (Ix) of the invention for the inhibitionof ITK are:—

-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (2-piperidin-1-yl-ethyl)-amide, Example 246(ab);-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    (pyridin-2-ylmethyl)-amide, Example 246(ac);-   2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid    [3-(4-methyl-piperazin-1-yl)-propyl]-amide, Example 246(ad);-   N-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide, Example    246(ae)-   N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide,    Example 253(c)-   and the corresponding N-oxides, and their prodrugs; and    pharmaceutically acceptable salts and solvates (e.g. hydrates) of    such compounds and their N-oxides and prodrugs.

The compounds of formula (Ix) of the invention exhibit usefulpharmacological activity and accordingly are incorporated intopharmaceutical compositions and used in the treatment of patientssuffering from certain medical disorders. The present invention thusprovides, according to a further aspect, compounds of formula (Ix) ofthe invention and compositions containing compounds of formula (Ix) ofthe invention for use in therapy.

Compounds of formula (Ix) within the scope of the present inventionblock kinase catalytic activity according to tests described in theliterature and in vitro procedures described hereinafter, and whichtests results are believed to correlate to pharmacological activity inhumans and other mammals. Thus, in a further embodiment, the presentinvention provides compounds of formula (Ix) of the invention andcompositions containing compounds of formula (Ix) of the invention foruse in the treatment of a patient suffering from, or subject to,conditions which can be ameliorated by the administration of proteinkinase inhibitors (e.g. Syk, KDR, tie2 or ITK). For example, compoundsof formula (Ix) of the present invention are useful in the treatment ofinflammatory diseases, for example asthma: atopic dermatitis,inflammatory dermatoses (e.g. psoriasis, dematitis herpetiformis,eczema, necrotizing and cutaneous vasculitis, bullous disease, acute andchronic urticaria,); allergic rhinitis and allergic conjunctivitis;joint inflammation, including arthritis, rheumatoid arthritis and otherarthritic conditions such as rheumatoid spondylitis, gouty arthritis,traumatic arthritis, rubella arthritis, psoriatic arthritis andosteoarthritis. The compounds of formula (Ix) are also useful in thetreatment of Chronic Obstructive Pulmonary Disease (COPD), adultrespiratory distress syndrome, silicosis, pulmonary sarcoidosis, acutesynovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis,atherosclerosis, peripheral vascular disease, cardiovascular disease,cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock,endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis,restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus,viral infections, bacterial infections, parasitic infections, graft vhost disease and other transplant associated rejection events,reperfusion injury, Crohn's disease and ulcerative colitis, cancers andtumours (such as colorectal, prostate, breast, thyroid, colon and lungcancers), atherosclerosis, degenerative muscle diseases, obesity,conjestive heart failure, Parkinson's, depression, schizophrenia,stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic painsyndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis,fibrotic diseases of the viscera, and inflammatory bowel disease.

The products of the present patent application as SYK inhibitors may beused for the treatment of diseases chosen from the following: asthma,allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronicobstructive pulmonary disease, adult respiratory distress syndrome,silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis,rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubellaarthritis, psoriatic arthritis, acute and chronic urticaria, cutaneousand systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxicshock, gram negative sepsis, diabetes, multiple sclerosis, systemiclupus erythromatosis, viral infections, bacterial infections, parasiticinfections, graft vs. host disease, organ transplant rejection,reperfusion injury, Crohn's disease and ulcerative colitis.

The products of the present patent application as KDR inhibitors may beused especially for the treatment or prevention of diseases chosen fromthe following group: cancers, especially breast, colon, lung andprostate cancer, atherosclerosis, degenerative muscle diseases, obesity,conjestive heart failure, Parkinson's, depression, schizophrenia,stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic painsyndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis andfibrotic diseases of the viscera.

A special embodiment of the therapeutic methods of the present inventionis the treating of asthma.

Another special embodiment of the therapeutic methods of the presentinvention is the treating of psoriasis.

Another special embodiment of the therapeutic methods of the presentinvention is the treating of joint inflammation.

Another special embodiment of the therapeutic methods of the presentinvention is the treating of inflammatory bowel disease.

Another special embodiment of the therapeutic methods of the presentinvention is the treating of cancers and tumours.

According to a further feature of the invention there is provided amethod for the treatment of a human or animal patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofa protein kinase inhibitor (e.g. Syk, KDR, tie2 or ITK) for exampleconditions as hereinbefore described, which comprises the administrationto the patient of an effective amount of compound of the invention or acomposition containing a compound of the invention. “Effective amount”is meant to describe an amount of compound of the present inventioneffective in inhibiting the catalytic activity a protein kinase, suchas. Syk, KDR, tie2 or ITK, and thus producing the desired therapeuticeffect.

References herein to treatment should be understood to includeprophylactic therapy as well as treatment of established conditions.

The present invention also includes within its scope pharmaceuticalcompositions comprising at least one of the compounds of formula (Ix) ofthe invention, as defined above, or a pharmaceutically acceptable saltor a prodrug, in association, where appropriate, with a pharmaceuticallyacceptable carrier or excipient.

Pharmaceutical compositions of the present invention for the treatmentof KDR or tie2 associated disease states can also, where appropriate,contain active principles of other antimitotic medicinal products suchas, in particular, those based on taxol, cis-platin, DNA-intercalatingagents and the like.

Compounds of formula (Ix) of the invention may be administered by anysuitable means. In practice compounds of formula (Ix) of the presentinvention may generally be administered parenterally, locally by topicalapplication to the skin and mucous membranes, rectally, orally, byinhalation, or by intravenous or intramuscular injection, especially bythe oral route.

Compositions according to the invention may be prepared according to thecustomary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavourings, colourings, or stabilisers in orderto obtain pharmaceutically acceptable preparations. The choice ofvehicle and the content of active substance in the vehicle are generallydetermined in accordance with the solubility and chemical properties ofthe active compound, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulfate and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilised by heating, irradiation ormicrofiltration.

For topical administration, gels (water or alcohol based), creams orointments containing compounds of formula (Ix) of the invention may beused. Compounds of formula (Ix) of the invention may also beincorporated in a gel or matrix base for application in a patch, whichwould allow a controlled release of compound through the transdermalbarrier.

For administration by inhalation compounds of formula (Ix) of theinvention may be dissolved or suspended in a suitable carrier for use ina nebuliser or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of the invention.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration and the durationof the treatment, and the condition of the patient. In the adult, thedoses are generally from about 0.001 to about 50, preferably about 0.001to about 5, mg/kg body weight per day by inhalation, from about 0.01 toabout 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg bodyweight per day by oral administration, and from about 0.001 to about 10,preferably 0.01 to 1, mg/kg body weight per day by intravenousadministration. In each particular case, the doses will be determined inaccordance with the factors distinctive to the subject to be treated,such as age, weight, general state of health and other characteristicswhich can influence the efficacy of the medicinal product.

The compounds of formula (Ix) according to the invention may beadministered as frequently as necessary in order to obtain the desiredtherapeutic effect. Some patients may respond rapidly to a higher orlower dose and may find much weaker maintenance doses adequate. Forother patients, it may be necessary to have long-term treatments at therate of 1 to 4 doses per day, in accordance with the physiologicalrequirements of each particular patient. Generally, the active productmay be administered orally 1 to 4 times per day. Of course, for somepatients, it will be necessary to prescribe not more than one or twodoses per day.

Compounds of formula (Ix) of the invention may be prepared by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature, for example thosedescribed by R. C. Larock in Comprehensive Organic Transformations, VCHpublishers, 1989.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Compounds of formula (Ix) wherein W, X, Y, Z and R¹ are as hereinbeforedefined for compounds of formula (Ix) and A₅ is H, may be prepared byreaction of compounds of formula (IIx):—

in which W, X, Y and Z are as hereinbefore defined for compounds offormula (Ix), with acids of formula (IIIx):—R¹—CO₂H  (IIIx)in which R¹ is as hereinbefore defined for compounds of formula (Ix), ata temperature at about 160° C. Alternatively the reaction may (i) becarried in the presence of hydrochloric acid at about refluxtemperature, or polyphosphoric acid at a temperature at about 160° C. or(ii) be carried out in a microwave oven.

Compounds of formula (Ix) wherein W, X, Y, Z and R¹ are as hereinbeforedefined and A₅ is H, may be prepared by reaction of compounds of formula(IIx) in which W, X, Y and Z are as hereinbefore defined for compoundsof formula (Ix), with aldehydes of formula (IVx):—R¹CHO  (IVx)in which R¹ is as hereinbefore defined for compounds of formula (Ix), inthe presence of in inert solvent, such as dimethylformamide ornitrobenzene, and at a temperature up to about 145° C. Alternatively thereaction may (i) be carried in the presence of sodium bisulfite at atemperature at about reflux temperature or (ii) be carried out in amicrowave oven at a temperature up to about 200° C.

Compounds of formula (Ix) wherein W, X, Y, Z and R¹ are as hereinbeforedefined for compounds of formula (Ix) and A₅ is H, may be prepared bycyclisation of compounds of formula (Vx):—

wherein W, X, Y, Z and R¹ are as hereinbefore defined for compounds offormula (Ix). The cyclisation may be carried out by heating in thepresence of an acid catalyst, such as acetic acid, and at a temperatureup to about 120° C.

Compounds of formula (Ixa) wherein W, X, Y and Z are as hereinbeforedefined for compounds of formula (Ix) and R¹ is

in which R⁹ is as hereinbefore defined for compounds of formula (Ix), R⁷is hydrogen and R⁸ is SR⁴, i.e. compounds of formula (Ixaa), may beprepared as shown in scheme 1.

For example diamines of formula (IIx), wherein W, X, Y and Z are ashereinbefore defined for compounds of formula (Ix), may be treated, inStep 1, with formic acid in the presence of hydrochloric acid at atemperature at about 50° C. The imino group of the resulting compoundsof formula (VIx) wherein W, X, Y and Z are as hereinbefore defined forcompounds of formula (Ix), may then be protected, in Step 2, with asuitable protecting group, for example when this is a2-(trimethylsilanyl)ethoxymethyl group the protection is convenientlycarried out by (i) reaction with sodium hydride in dimethylformamidethen (ii) reaction with 2-(trimethylsilanyl)ethoxymethyl chloride. Theresulting compounds of formula (VIIx), wherein W, X, Y and Z are ashereinbefore defined for compounds of formula (Ix) and R¹¹ is a suitableprotecting group, such as a 2-(trimethylsilanyl)ethoxymethyl group, maythen be treated, in Step 3, with (i) lithium diisopropylamide, in aninert solvent, such as tetrahydrofuran, and at a temperature at about−78° C., then (ii) acetamides of formula R⁹—C(═O)—N(CH₃)₂ [in which R⁹is as hereinbefore defined for compounds of formula (Ix)]. The resultingcompounds of formula (Xx), wherein W, X, Y, Z, R⁹ and R¹¹ are ashereinbefore defined for compounds of formula (Ix), [alternativelyprepared by (i) reaction of diamines of formula (IIx) withβ-hydroxy-acids of formula R⁹CH₂CH(OH)CO₂H [in which R⁹ is ashereinbefore defined for compounds of formula (Ix)], in Step 1a, at atemperature at about 70° C., (ii) oxidation, in Step 2a, of theresulting compounds of formula (VIIIx) with manganese dioxide in aninert solvent, such as chloroform, and at a temperature at about 60° C.and (iii) protection of the imino group, in Step 3a, as described inStep 2 above)] may then be treated, in Step 4, with (i) sodium tertiarybutoxide, in an inert solvent, such as benzene or tetrahydrofuran, at−5° C., then (ii) carbon disulfide and then (iii) compounds of formulaR⁴—X¹ [in which R⁴ is as hereinbefore defined for compounds of formula(Ix)] and X¹ is halo. The resulting compounds of formula (XIx), whereinW, X, Y, Z, R⁴, R⁹ and R¹¹ are as hereinbefore defined for compounds offormula (Ix), may then be treated, in Step 5, with hydrazine, in aninert solvent, such as ethanol, and at a temperature from about roomtemperature to about reflux temperature. The resulting compounds offormula (XIIx), wherein W, X, Y, Z, R⁴, R⁹ and R¹¹ are as hereinbeforedefined for compounds of formula (Ix), may then be deprotected {forexample when R¹¹ is a 2-(trimethylsilanyl)ethoxymethyl group bytreatment with hydrochloric acid in an inert solvent, such as ethanol,and at a temperature from about room temperature to about refluxtemperature}, in Step 6, to liberate the pyrazoles of general formula(Ixaa), wherein W, X, Y, Z, R⁴ and R⁹ are as hereinbefore defined forcompounds of formula (Ix). Compounds of formula (XIx) in which R¹¹ is atetrahydropyran-2-yl protecting group may be deprotected by treatmentwith an acid, such as p-toluenesulfonic acid, in water at refluxtemperature and subsequently treated with hydrazine, in an inertsolvent, such as ethanol, and at a temperature from about roomtemperature to about reflux temperature to give pyrazoles of generalformula (Ixaa), wherein W, X, Y, Z, R⁴ and R⁹ are as hereinbeforedefined for compounds of formula (Ix).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbeforedefined for compounds of formula (Ix) and A₅ is H, and R¹ is

in which R⁹ is as hereinbefore defined for compounds of formula (Ix), R⁷is hydrogen and R⁸ is OR⁴, i.e. compounds of formula (Ixab), may beprepared as shown in scheme 2.

For example compounds of formula (XIx), wherein W, X, Y, Z, R⁹, R¹¹ areas hereinbefore defined for compounds of formula (Ix), and R⁴ is loweralkyl, may be treated, in Step 1, with the sodium salt of an alcohol offormula R⁴—OH (in which R⁴ is lower alkyl), such as sodium ethoxide,followed by treatment with hydrazine as described hereinabove forscheme 1. The resulting compounds of formula (XIIIx), wherein W, X, Y,Z, R⁴, R⁹ and R¹¹ are as hereinbefore defined for compounds of formula(Ix), may then be deprotected [for example when R¹¹ is a2-(trimethylsilanyl)ethoxymethyl group by treatment with trifluoroaceticacid at about 50° C.], in Step 2, to liberate the pyrazoles of generalformula (Ixab).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbeforedefined for compounds of formula (Ix) and A₅ is H, and R¹ is

in which R⁹ is as hereinbefore defined for compounds of formula (Ix), R⁷is hydrogen and R⁸ is —NY¹Y², i.e. compounds of formula (Ixac), may beprepared as shown in scheme 3.

For example compounds of formula (XIx), wherein W, X, Y, Z. R⁹ and R¹¹are as hereinbefore defined for compounds of formula (Ix), and R⁴ islower alkyl, may be treated, in Step 3, with an amine of formula HNY¹Y²[in which Y¹ and Y² are as hereinbefore defined for compounds of formula(Ix)], e.g. morpholine. The resulting compounds of formula (XIVx),wherein W. X, Y. Z. R⁹, R¹¹, Y¹ and Y² are as hereinbefore defined forcompounds of formula (Ix), and R⁴ is lower allyl, may then be treated,in step 2, with hydrazine as described hereinabove for scheme 1. Theresulting compounds of formula (XVx), wherein W, X, Y, Z, R⁹, R¹¹, Y¹and Y² are as hereinbefore defined for compounds of formula (Ix), maythen be deprotected as described hereinabove, in Step 3, to liberate thepyrazoles of general formula (Ixac).

Compounds of formula (Ix) wherein W, X, Y and Z are as hereinbeforedefined for compounds of formula (Ix) and A₅ is H, and R¹ is

i.e. compounds of formula (Ixad), may be prepared as shown in scheme 4.

For example compounds of formula (XIx), wherein W, X, Y, Z, R⁹ and R¹¹are as hereinbefore defined for compounds of formula (Ix), and R⁴ islower alkyl, may be treated, in Step 1, with hydroxylamine in thepresence of sodium methoxide and in methanol at reflux temperature. Theresulting compounds of formula (XVIx), wherein W, X, Y, Z, R⁴, R⁹ andR¹¹ are as hereinbefore defined for compounds of formula (Ix), may thenbe deprotected as described hereinabove, in Step 2, to liberate theisoxazoles of general formula (Ixad).

Compounds of the invention of formula (Ix) may also be prepared byinterconversion of other compounds of the invention.

Thus, for example, compounds of formula (Ix) containing a carboxy groupmay be prepared by hydrolysis of the corresponding esters. Thehydrolysis may conveniently be carried out by alkaline hydrolysis usinga base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or analkali metal carbonate, e.g. potassium carbonate, in the presence of anaqueous/organic solvent mixture, using organic solvents such as dioxan,tetrahydrofuran or methanol, at a temperature from about ambient toabout reflux. The hydrolysis of the esters may also be carried out byacid hydrolysis using an inorganic acid, such as hydrochloric acid, inthe presence of an aqueous/inert organic solvent mixture, using organicsolvents such as dioxan or tetrahydrofuran, at a temperature from about50° C. to about 80° C.

As another example compounds of formula (Ix) containing a carboxy groupmay be prepared by acid catalysed removal of the tert-butyl group of thecorresponding tert-butyl esters using standard reaction conditions, forexample reaction with trifluoroacetic acid at a temperature at aboutroom temperature.

As another example compounds of formula (Ix) containing a carboxy groupmay be prepared by hydrogenation of the corresponding benzyl esters. Thereaction may be carried out in the presence of ammonium formate and asuitable metal catalyst, e.g. palladium, supported on an inert carriersuch as carbon, preferably in a solvent such as methanol or ethanol andat a temperature at about reflux temperature. The reaction mayalternatively be carried out in the presence of a suitable metalcatalyst, e.g. platinum or palladium optionally supported on an inertcarrier such as carbon, preferably in a solvent such as methanol orethanol.

As another example compounds of formula (Ix) containing a carboxy groupmay be prepared by treatment of compounds of formula I(x) containing acyano group with hydrochloric acid in acetic acid at a temperature atabout 100° C.

As another example of the interconversion process, compounds of formula(Ix) containing a —C(═O)—NY¹Y² group may be prepared by reaction ofcompounds of formula (Ix) containing a carboxy group with an amine offormula HNY¹Y² to give an amide bond using standard peptide couplingprocedures, for example coupling in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydroxybenzotriazole anddi-isopropylethylamine in an inert solvent, such as dimethylformamideand a temperature up to about 80° C. The reaction may alternatively becarried out in the presence ofO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate and triethylamine (or diisopropylethylamine) intetrahydrofuran (or dimethylformamide) at room temperature.

As another example of the interconversion process, compounds of formula(Ix) containing a —NH—C(═O)—R⁴ group may be prepared by: (i) couplingcompounds of formula (Ix) containing an amino group with acids offormula R⁴—CO₂H using standard coupling conditions as described above;or (ii) by reaction of compounds of formula (Ix) containing an aminogroup with acid chlorides of formula R⁴—C(═)O—Cl in the presence of atertiary base, such as di-isopropylethylamine, in an inert solvent, sucha dichloromethane, and at a temperature at about room temperature. Insome instances a bis-acylated derivative is obtained by reaction ofcompounds of formula (Ix) containing an amino group and in which A₅ isH, with acid chlorides of formula R⁴—C(═)O—Cl. These bis-acylatedderivatives may be converted to compounds of formula (Ix) containing a—NH—C(═O)—R⁴ group and in which A₅ is H, by treatment with potassiumhydroxide in aqueous methanol at a temperature at about 60° C.

As another example of the interconversion process, compounds of formula(Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is —C(═O)R⁴) may be prepared by reaction of compounds offormula (Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is hydrogen) with acid chlorides of formula R⁴—C(═O)—Cl in thepresence of a tertiary base, such as di-isopropylethylamine, in an inertsolvent, such a dichloromethane, and at a temperature at about roomtemperature.

As another example of the interconversion process, compounds of formula(Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is —C(═O)NY¹Y²) may be prepared by reaction of compounds offormula (Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is hydrogen) with carbamoyl chlorides of formulaY¹Y²N—C(═O)—Cl in the presence of a tertiary base, such asdiisopropylethylamine, in an inert solvent, such a dichloromethane, andat a temperature at about room temperature.

As another example of the interconversion process, compounds of formula(Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is —C(═O)OR⁴) may be prepared by reaction of compounds offormula (Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is hydrogen) with chloroformates of formula R⁴O—C(═O)—Cl inthe presence of a tertiary base, such as diisopropylethylamine, in aninert solvent, such a dichloromethane, and at a temperature at aboutroom temperature.

As another example of the interconversion process, compounds of formula(Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is —SO₂R⁴) may be prepared by reaction of compounds of formula(Ix) wherein R¹ is a pyrazolyl moiety

in which R⁸ and R⁹ together with the carbon atoms to which they areattached form a 5 or 6 membered heterocyclic ring containing a NY⁵ group(where Y⁵ is hydrogen) with sulfonyl chlorides of formula R⁴SO₂—Cl inthe presence of a tertiary base, such as diisopropylethylamine, in aninert solvent, such a dichloromethane, and at a temperature at aboutroom temperature.

As another example of the interconversion process, compounds of formula(Ix) containing a —NH—C(═O)—R⁴ group, in which R⁴ is alkyl substitutedby NY¹Y², may be prepared by (i) coupling compounds of formula (Ix)containing an amino group with the appropriate chloroalkyl acidchloride, in the presence of a tertiary base, such asdi-isopropylethylamine, in an inert solvent, such a dichloromethane, andat a temperature at about room temperature, followed by (ii) reactionwith an amine of formula HNY¹Y².

As another example of the interconversion process, compounds of formula(Ix) containing a —N(R⁶)C(═O)NY¹Y² group [in which R⁶ is hydrogen, Y¹ ishydrogen and Y² is alkenyl, aryl, cycloalkyl, heteroaryl, or optionallysubstituted alkyl] may be prepared by reaction of compounds of formula(Ix) containing an amino group with isocyanates of formula Y²N═C═O [inwhich Y² is alkenyl, aryl, cycloalkyl, heteroaryl, or optionallysubstituted alkyl], in an inert solvent, such as tetrahydrofuran, and ata temperature at about room temperature.

As another example of the interconversion process, compounds of formula(Ix) containing a —N(R⁶)C(═O)NY¹Y² group [in which R⁶ is hydrogen] maybe prepared by reaction of compounds of formula (Ix) containing an aminogroup with 1,1-carbonyldiimidazole in an inert solvent such astetrahydrofuran and at a temperature at about 60° C. followed byreaction with an amine of formula HNY¹Y².

As another example of the interconversion process, compounds of formula(Ix) containing an amino group may be prepared by reduction of thecorresponding compounds of formula (Ix) containing a nitro group. Forexample, the reduction may conveniently be carried out by hydrogenationin the presence of a suitable metal catalyst, e.g. platinum or palladiumoptionally supported on an inert carrier such as carbon, preferably in asolvent such as methanol or ethanol. The reduction may also convenientlybe carried out by means of reaction with tin chloride, in an inertsolvent, such as methanol or ethanol, and at a temperature at aboutreflux temperature. Alternatively the reaction with tin chloride may becarried out in a microwave oven at a temperature at about 140° C.

As another example of the interconversion process, compounds of formula(Ix) containing a —CH₂OH group may be prepared by the reduction ofcorresponding compounds of formula (Ix) containing a —CHO or —CO₂ loweralkyl group. For example, the reduction may conveniently be carried outby means of reaction with lithium aluminium hydride, in an inertsolvent, such as tetrahydrofuran, and at a temperature from about roomtemperature to about reflux temperature.

As another example of the interconversion process, compounds of formula(Ix) containing a —CH(OH)R⁴ group may be prepared by treating compoundsof formula (Ix) containing a —C(═O)R⁴ group with diisobutylaluminiumhydride, in an inert solvent, such as tetrahydrofuran, and at atemperature from about −78° C. to about room temperature.

As another example of the interconversion process, compounds of formula(Ix) in which R¹ is aryl or heteroaryl substituted by hydroxy may beprepared by reaction of the corresponding compounds of formula (Ix) inwhich R¹ is aryl or heteroaryl substituted by methoxy with a Lewis acid,such as boron tribromide, in an inert solvent, such as dichloromethane,and at a temperature from about 0° C. to about room temperature.

As another example of the interconversion process, compounds of formula(Ix) containing sulfoxide linkages may be prepared by the oxidation ofcorresponding compounds containing —S— linkages. For example, theoxidation may conveniently be carried out by means of reaction with aperoxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inertsolvent, e.g. dichloromethane, preferably at or near room temperature,or alternatively by means of potassium hydrogen peroxomonosulfate in amedium such as aqueous methanol, buffered to about pH 5, at temperaturesbetween about 0° C. and room temperature. This latter method ispreferred for compounds containing an acid-labile group.

As another example of the interconversion process, compounds of formula(Ix) containing sulfone linkages may be prepared by the oxidation ofcorresponding compounds containing —S— or sulfoxide linkages. Forexample, the oxidation may conveniently be carried out by means ofreaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably inan inert solvent, e.g. dichloromethane, preferably at or near roomtemperature.

As another example of the interconversion process, compounds of formula(Ix) containing a cyano group may be prepared by reaction of thecorresponding compounds of formula (Ix) containing a —C(═O)—NH₂ groupwith phosphorus pentachloride in the presence of triethylamine. Thereaction may conveniently be carried out in an inert solvent, such astetrahydrofuran, and at a temperature at about reflux temperature.

As another example of the interconversion process, compounds of formula(Ix) containing a —C(═O)NH₂ group may be prepared by reaction of thecorresponding compounds of formula (Ix) containing a cyano group withhydrogen peroxide in the presence of sodium hydroxide. The reaction mayconveniently be carried out in methanol at a temperature at about roomtemperature. Alternatively compounds of formula (Ix) containing a—C(═O)—NH₂ group may be prepared by reaction of the correspondingcompounds of formula (Ix) containing a cyano group with hydrochloricacid in acetic acid at a temperature from about 80° C. to about 100° C.

As another example of the interconversion process, compounds of formula(Ix) containing a tetrazolyl group may be prepared by reaction of thecorresponding compounds of formula (Ix) containing a cyano group withazidotributyltin. The reaction may conveniently be carried out in aninert solvent, such as toluene, and at a temperature at about refluxtemperature.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention may be prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention may be prepared either by dissolving the free base inwater or aqueous alcohol solution or other suitable solvents containingthe appropriate acid and isolating the salt by evaporating the solution,or by reacting the free base and acid in an organic solvent, in whichcase the salt separates directly or can be obtained by concentration ofthe solution.

Compounds of this invention can be regenerated from their acid additionsalts by the application or adaptation of known methods. For example,parent compounds of the invention can be regenerated from their acidaddition salts by treatment with an alkali, e.g. aqueous sodiumbicarbonate solution or aqueous ammonia solution.

According to a further feature of the invention, base addition salts ofthe compounds of this invention may be prepared by reaction of the freeacid with the appropriate base, by the application or adaptation ofknown methods. For example, the base addition salts of the compounds ofthis invention may be prepared either by dissolving the free acid inwater or aqueous alcohol solution or other suitable solvents containingthe appropriate base and isolating the salt by evaporating the solution,or by reacting the free acid and base in an organic solvent, in whichcase the salt separates directly or can be obtained by concentration ofthe solution.

Compounds of this invention can be regenerated from their base additionsalts by the application or adaptation of known methods. For example,parent compounds of the invention can be regenerated from their baseaddition salts by treatment with an acid, e.g. hydrochloric acid.

Compounds of the present invention may be conveniently prepared, orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallisation from an aqueous/organic solvent mixture,using organic solvents such as dioxan, tetrahydrofuran or methanol.

The starting materials and intermediates may be prepared by theapplication or adaptation of known methods, for example methods asdescribed in the Reference Examples or their obvious chemicalequivalents.

Intermediates of formula (IIx), wherein W, X, Y and Z are ashereinbefore defined for compounds of formula (Ix), may be prepared byreduction of the corresponding nitro compounds of formula (1):

wherein W, X, Y and Z are as hereinbefore defined for compounds offormula (Ix). For example, the reduction may conveniently be carried outby means of reaction with tin chloride, in an inert solvent, such asmethanol or ethanol, and at a temperature at about reflux temperature.Alternatively the reaction may be carried out in a microwave oven at atemperature at about 140° C.

Intermediates of formula (IIx), wherein W, X, Y and Z are ashereinbefore defined for compounds of formula (Ix), may also be preparedby reduction of the corresponding dinitro compounds of formula (2):

wherein W, X, Y and Z are as hereinbefore defined for compounds offormula (Ix), with tin chloride as above.

Nitro compounds of formula (1), wherein W is CH, X is C—R², Y is C—R³and Z is CH [in which R³ is as hereinbefore defined for compounds offormula (Ix)], may be prepared from the corresponding anilines offormula (3)

wherein X is C—R² and Y is C—R³ [in which R³ is as hereinbefore definedfor compounds of formula (Ix)], by (i) reaction with acetic anhydride inthe presence of triethylamine, in an inert solvent, such asdichloromethane, and at a temperature from about 0° C. to about roomtemperature, (ii) reaction with nitric acid in the presence of aceticacid and acetic anhydride at a temperature at about −5° C. and (iii)reaction with an alkali metal alkoxide, such as sodium methoxide, inmethanol and at room temperature.

Nitro compounds of formula (1), wherein W is CH, X is C—R² (in which R²is alkyl), Y is C—R³ (in which R³ is an aryl or heteroaryl group) and Zis CH may be prepared by reaction of compounds of formula (4):

wherein X is C—R² (in which R² is alkyl) and X² is bromo or iodo, withan aryl (or heteroaryl) boronic acid in the presence of a suitablecatalyst, such as tetrakis(triphenylphosphine)palladium, in an inertsolvent, such as tetrahydrofuran, and at a temperature at about 85° C.

Intermediates of formula (IIIx), wherein R¹ is

in which R⁷ is hydrogen, R⁸ is alkyl and R⁹ is hydrogen or alkyl may beprepared by reaction of compounds of formula (5):

wherein R⁸ is alkyl and R⁹ is hydrogen, with hydrazine in the presenceof acetic acid at reflux temperature, followed by hydrolysis.

Intermediates of formula (IIIx), wherein R¹ is

in which R⁷ is hydrogen and R⁸ and R⁹ together with the carbon atoms towhich they are attached form a 5, 6 or 7 membered carbocyclic ring maybe similarly prepared by reaction of compounds of formula (5) wherein R⁸and R⁹ together with the carbon atoms to which they are attached form a5, 6 or 7 membered carbocyclic ring, with hydrazine, followed byhydrolysis.

Intermediates of formula (IIIx), wherein R¹ is

in which R⁷ is hydrogen, R¹³ is alkyl and X¹ is O, S, SO₂, or NY⁵ (whereY⁵ is R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴) may be similarlyprepared by reaction of compounds of formula (6):

wherein R¹³ is alkyl and X¹ is O, S, SO₂, or NY⁵ (where Y⁵ is R⁴,—C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴), with hydrazine, followed byhydrolysis.

Compounds of formula (5), wherein R⁸ is alkyl and R⁹ is hydrogen, may beprepared by reaction of compounds of formula (7):

wherein R⁸ is alkyl, with diethyl oxalate, in the presence of an alkalimetal alkoxide, such as sodium ethoxide, in an inert solvent, such asethanol, and at a temperature at about 60° C.

Compounds of formula (5), wherein R⁸ and R⁹ together with the carbonatoms to which they are attached form a 5, 6 or 7 membered carbocyclicring may be similarly prepared by reaction of cyclopentanone, orcyclohexanone, with diethyl oxalate.

Compounds of formula (6), wherein R¹³ is alkyl and X¹ is O, S, SO₂, orNY⁵ (where Y⁵ is R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴) may besimilarly prepared by reaction of compounds of formula (8):

wherein R¹³ is alkyl and X¹ is O, S, SO₂, or NY⁵ (where Y⁵ is R⁴,—C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴), with diethyl oxalate.

Intermediates of formula (IVx), wherein R¹ is as hereinbefore definedfor compounds of formula (Ix), may be prepared by oxidation of compoundsof formula (9):R¹—CH₂OH  (9)wherein R¹ is as hereinbefore defined for compounds of formula (Ix). Theoxidation may conveniently be carried out with manganese dioxide, orpyridinium chlorochromate, in an inert solvent, such as chloroform, ordichloromethane, and at a temperature at about 60° C. This procedure isparticularly suitable for intermediates of formula (IVx) wherein R¹ is

(in which R¹⁰ and p are as hereinbefore defined).

Compounds of formula (9), wherein R¹ is as hereinbefore defined forcompounds of formula (Ix), may be prepared by reduction of acids offormula (10):R¹—CO₂H  (10)wherein R¹ is as hereinbefore defined for compounds of formula (Ix). Thereduction may conveniently be carried out with lithium aluminiumhydride, in an inert solvent, such as tetrahydrofuran, and at atemperature at about room temperature.

Compounds of formula (9), wherein R¹ is as hereinbefore defined forcompounds of formula (Ix), may be prepared by reduction of alkyl estersof formula (10a):R¹—CO₂alkyl  (10a)wherein R¹ is as hereinbefore defined for compounds of formula (Ix). Thereduction may conveniently be carried out with lithium aluminiumhydride, in an inert solvent, such as tetrahydrofuran, and at atemperature at about room temperature.

Acids of formula (10), wherein R¹ is

(in which R¹⁰ and p are as hereinbefore defined), may be prepared byreaction of indole-diones of formula (11):

wherein R¹⁰ and p are as hereinbefore defined, with (i) sodium hydroxideat 50° C., (ii) sodium nitrite then sulfuric acid at 5° C. and (iii) tin(II) chloride.

Indole-diones of formula (11), wherein R¹⁰ is as hereinbefore definedand p is one, may be prepared by reaction of compounds of formula (12):

wherein R¹⁰ is as hereinbefore defined, with polyphosphoric acid at atemperature at about 80° C.

Compounds of formula (12), wherein R¹⁰ is as hereinbefore defined, maybe prepared by reaction of anilines of formula (13):

wherein R¹⁰ is as hereinbefore defined, with chloral hydrate andhydroxylamine in the presence of hydrochloric acid at a temperature atabout 80° C.

Intermediates of formula (Vx), wherein W, X, Y, Z and R¹ are ashereinbefore defined for compounds of formula (Ix), may be prepared byreaction of compounds of formula (1) with acid chlorides of formulaR¹—C(═O)—Cl, optionally in the presence of a tertiary base, such aspyridine, and in an inert solvent, such as dichloromethane, at atemperature at about room temperature.

The following references are also cited, which may be used for thepreparation of benzimidazoles, pyrazoles or indazoles in the context ofthe present invention:

-   G. R. Newkome, W. W. Paudler, Comtemporary Heterocyclic Chemistry,    Syntheses, Reactions and Applications, J. Wiley, 1982-   Preston, Heterocyclic Compounds, Benzimidazoles and congeneric    tricyclic compounds, J. Wiley, 1981-   Behr, Fusco, Jarboe, Heterocyclic Compounds, Pyrazoles, Pyrazolines,    Pyrazolidines, indazoles and condensed rings, J. Wiley, 1967.

The following schemes, schemes 5 to 13, illustrate the synthesis ofspecific examples within the specification using the processeshereinbefore described with the use of appropriate protecting groupswhere necessary.

The present invention is further exemplified but not limited by thefollowing illustrative Examples and Reference Examples.

400M Hz ¹H nuclear magnetic resonance spectra (NMR) were recorded on aVarian Unity INOVA machine. In the nuclear magnetic resonance spectra(NMR) the chemical shifts (δ) are expressed in ppm relative totetramethylsilane. Abbreviations have the following significances:s=singlet; d=doublet; t=triplet; m=multiplet; q=quartet; dd=doublet ofdoublets; ddd=doublet of double doublets.

The thin layer chromatography (TLC) RF values were determined usingMerck silica plates.

High Pressure Liquid Chromatography-Mass Spectrometry (LC-MS) conditionsfor determination of retention times (R_(T)) and associated mass ionswere as follows:—

Method A:

-   -   Mass Spectrometer (MS)—LCT Time-of-Flight (Micromass UK Ltd)        Serial No. KA014 [Ionization Mode: Electrospray (Positive Ion);        Scan: Tof MS (Full Scan m/z 100-1200, sum for 0.4 s @ 50        us/scan) Centroid Mode]. Liquid Chromatograph (LC): Hewlett        Packard HP1100 Series Binary Pump (Serial # US80301343)&        Degasser (serial # JP73008973). Hypersil BDS C-18, 3μ (4.6 mm×50        mm), Reverse Phase Column operated under gradient elution        conditions using (A) water containing 0.05% trifluoroacetic acid        and (B) acetonitrile containing 0.05% trifluoroacetic acid as        the mobile phase (gradient: 0.00 minutes, 100% A; linear        gradient to 100% B at 2 minutes; then hold until 1.5 minutes);        flow rate 1 ml/minute to column & to UV detector, flow split        after UV detector such that 0.75 ml/minute to ELS detector and        0.25 ml/minute to mass spectrometer; injection volume 10 μl;        Auxiliary Detectors: (i) Hewlett Packard Model BP1100 Series UV        detector (serial # JP73704703) wavelength=220 nm; (ii) Sedere        (France) Model SEDEX 75 Evaporative Light Scattering (ELS)        detector (serial # 9970002A); temperature=46° C., Nitrogen        pressure=4 bar; Autosampler/Injector: Gilson Model 215 Liquid        Handler with Model 819 injection valve (serial # 259E8280).        Method B:    -   Waters Symmetry C8 3.5 μm HPLC column operated under gradient        conditions with mixtures of (A) water containing 0.1% formic        and (B) acetonitrile containing 0.1% formic acid as the mobile        phase (gradient: 0.00 minutes, 95% A:5% B; 0.75 minutes, 95%        A:5% B; 3.00 minutes 100% B; 4.00 minutes 100% B; 4.25 minutes        95% A:5% B); flow rate 1.5 ml/minute with approximately 200        μl/minute split to the Mass Spectrometer; injection volume 20        μl; in line Diode Array (210-300 nm), in line Evaporative light        scattering (ELS) detection ELS—temperature 40° C., Gain 7-1.5        m/minute; Source temperature 150° C.        Method C:    -   Waters Symmetry C8 3.5 μm HPLC column operated under gradient        conditions with mixtures of (A) water containing 10 mM ammonium        acetate and (B) methanol containing 10 mM ammonium acetate as        the mobile phase (gradient: 0.00 minutes, 95% A:5% B; 0.75        minutes, 95% A:5% B; 3.00 minutes 100% B; 4.00 minutes 100% B;        4.25 minutes 95% A:5% B); flow rate 1.5 mL/minute with        approximately 200 μl/minute split to the Mass Spectrometer;        injection volume 20 μl; in line Diode Array (210-300 nm), in        line Evaporative light scattering (ELS) detection        ELS—temperature 40° C., Gain 7-1.5 ml/minute; Source temperature        150° C.        Method D:    -   C8 Phenomenex Luna 5 μm (250×4.6 mm) HPLC column operated under        gradient conditions with mixtures of (A) methanol containing 10        mM ammonium acetate and (B) water containing 10 mM ammonium        acetate as the mobile phase (gradient: 0 to 2 minutes 10% A:90%        B; 2 to 23 minutes ramp up to 100% A; 23 to 30 minutes 100% A;        30 to 37 minutes 10% A:90% B); flow rate 1 ml/minute.        Method E:    -   Mass Spectrometer (MS)—LCT Time-of-Flight (Micromass UK Ltd)        Serial No. KA014 [Ionization Mode: Electrospray (Positive Ion);        Scan: Tof MS (Full Scan m/z 100-1200, sum for 0.4 s @ 50        us/scan) Centroid Mode]. Liquid Chromatograph (LC): Hewlett        Packard HP1100 Series Binary Pump (Serial # US80301343)&        Degasser (serial # JP73008973). Synergi 2U Hydro reverse phase        20×4 mm column. solvent A 0.1% trifluoroacetic acid in water,        Solvent B 0.1% trifluoroacetic acid in acetonitrile. Gradient 5%        B at time 0 to 90% B at time 2 minutes to 100% B at 5 minutes;        flow rate 1 ml/minute to column & to UV detector, flow split        after UV detector such that 0.75 m/minute to ELS detector and        0.25 ml/minute to mass spectrometer; injection volume 10 μl;        Auxiliary Detectors: (i) Hewlett Packard Model HP1100 Series UV        detector (serial # JP73704703) wavelength=220 nm; (ii) Sedere        (France) Model SEDEX 75 Evaporative Light Scattering (ELS)        detector (serial # 9970002A); temperature=46° C., Nitrogen        pressure=4 bar; Autosampler/Injector: Gilson Model 215 Liquid        Handler with Model 819 injection valve (serial # 259E8280).        Method F:    -   Agilent 1100 Series HPLC with a YMC CombiScreen Pro C18 5.5 μm        4.6 mm by 33 mm reverse phase column using gradient elution with        a mixture of (A) acetonitrile/0.1% trifluoroacetic acid and (B)        water/0.1% trifluoroacetic acid (5% A:95% B to 95% A:5% B over        5.1 minutes) with a 1.2 mL/minute flow rate; Agilent 1100 Series        wellplate autosampler with 2 μL injection; Agilent 1100 Series        diode array detector with 215, 254 and 300 nM wavelength        detection; Hewlett Packard 1100 Series mass spectrometer with        electrospray and positive ionisation.        Method G:    -   Rainin HPXL dual pump HPLC system with a Rainin Dynamax UV-D II        detector for 254 nM wavelength, C18 Metachem Monochrom 10 μM        (100×4.6 mm) column using gradient elution with a mixture of (A)        water with 0.1% trifluoroacetic acid and (B) acetonitrile as the        mobile phase (90% A:10% B to 0% A in 12 minutes) with a flow        rate of 1.0 ml/minute C18 Phenomenex Luna 5 μM (150×4.6 mm)        column using gradient elution with a mixture of (A) methanol        and (B) water with 10 mM ammonium acetate as the mobile phase        (0-2 minutes 10% A:90% B; 2-25 minutes ramp up to 100% A; 25-32        minutes 100% A; 32-33 minutes 10% A:90% B) with a flow rate of        1.0 ml/minute.        Method H:    -   Waters Symmetry C8 3.5CM Column (50×4.6 mm) using gradient        elution with a mixture of (A) water/0.1% formic acid and (B)        acetonitrile/0.1% formic acid (5% B:95% A to 100% B in 3.5 min,        100% B for 1 min, 100% B to 5% B:95% A in 0.1 min, Equilibrate        5% B:95% A 0.49 minutes, Total run time 5 min)with a flow rate        of 1.5 mL/minute; Detection 210-300 nM, 2 nM range interval;        Column Temp 30° C.; Mass Spec Quadrupole, Electrospray, cone        voltage 25V, +/−ion switching, centroid data, 140 to 850 Da, 0.6        sec scan, 0.4 sec inter scan delay.        Method J:    -   Waters Symmetry C8 3.5 μM Column (50×4.6 mm) using gradient        elution with a mixture of (A) 0.1% formic acid in water and (B)        0.1% formic acid in acetonitrile (5% B:95% A 0.75 minutes to        100% B in 4 minutes, 100% B for 0.5 minutes, 100% B to 5% B:95%        A in 1 minute, Total run time 5 minutes with a flow rate of 1.5        mL/minute; Detection 210-300 nM, 2 nM range interval; Column        Temp 30° C.; Mass Spec Quadrupole, Electrospray, cone voltage        25V, +/−ion switching, centroid data, 140 to 850 Da, 0.6 sec        scan, 0.4 sec inter scan delay.        Method K:    -   Waters Symmetry C8 3.5μ Column (50×4.6 mm) using gradient        elution with a mixture of (A) 10 mM ammonium acetate in water        and (B) 10 mM ammonium acetate in methanol (5% B:95% A 0.75        minutes to 100% B in 4 minutes, 100% B for 0.5 minutes, 100% B        to 5% B:95% A in 1 minute, Total run time 5 min)with a flow rate        of 1.5 mL/minute; Detection 210-300 nM, 2 nm range interval;        Column Temp 30° C.; Mass Spec Quadrupole, Electrospray, cone        voltage 25V, +/−ion switching, centroid data, 140 to 850 Da, 0.6        sec scan, 0.4 sec inter scan delay.        Method L:    -   Phenomenex Luna C18(2) 3 μM Column (150×4.6 mm) using gradient        elution with a mixture of (A) 0.1% formic acid in water and (B)        0.1% formic acid in acetonitrile (20% B:80% A to 100% B in 10        minutes, 100% B for 2 minutes, 100% B to 20% B:80% A in 0.5        minutes, 20% B:80% A for 3.5 minutes, Total run time 16 minutes        with a flow rate of 1.0 mL/minute; 210-300 nM, 220 and 254 nM        extracted and ELSD; Column Temp 30° C.; Mass Spec Quadrupole,        Electrospray, cone voltage 25V, +/−ion switching, centroid data,        100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan delay.        Method M:    -   Phenomenex Luna C18(2) 3 μM Column (150×4.6 mm) using gradient        elution with a mixture of (A) 0.1% formic acid in water and (B)        0.1% formic acid in acetonitrile (5% B:95% A to 60% B:40% A in        10 minutes, 60% B:40% A for 2 minutes, 60% B:40% A to 5% B:95% A        in 0.5 minutes, 5% B:95% A for 3.5 minutes, Total run time 16        minutes with a flow rate of 1.0 mL/minute; 210-300 nM, 220 and        254 nM extracted and ELSD; Column Temp 30° C.; Mass Spec        Quadrupole, Electrospray, cone voltage 25V, +/−ion switching,        centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan        delay.        Method N:    -   Waters Symmetry C8 3.5 μM Column (50×4.6 mm) using gradient        elution with a mixture of (A) 10 mM ammonium acetate in water        and (B) 10 mM ammonium acetate in methanol (5% B:95% A to 100% B        in 3.5 minutes, 100% B for 1 minute, 100% B to 5% B:95% A in 0.1        minute, Equilibrate 5% B:95% A 0.49 minutes, Total run time 5        minutes)with a flow rate of 1.5 mL/minute; Detection 210-300 nM,        2 nM range interval; Column Temp 30° C.; Mass Spec Quadrupole,        Electrospray, cone voltage 25V, +/−ion switching, centroid data,        140 to 850 Da, 0.6 sec scan, 0.4 sec inter scan delay.        Method P:    -   Phenomenex Luna C18(2) 3 μM Column (150×4.6 mm) using gradient        elution with a mixture of (A) 10 mm ammonium acetate in water        and (B) 10 mm ammonium acetate in methanol (5% B:95% A to 60%        B:40% A in 10 minutes, 60% B:40% A for 2 minutes, 60% B:40% A to        5% B:95% A in 0.5 minutes, 5% B:95% A for 3.5 minutes, Total run        time 16 minutes with a flow rate of 1.0 mL/minute; 210-300 nM,        220 and 254 nM extracted and ELSD; Column Temp 30° C.; Mass Spec        Quadrupole, Electrospray, cone voltage 25V, +/−ion switching,        centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan        delay.        Method Q:    -   Phenomenex Luna C18(2) 3 μM Column (150×4.6 mm) using gradient        elution with a mixture of (A) 10 mm ammonium acetate in water        and (B) 10 mm ammonium acetate in methanol (20% B:80% A to 100%        B in 10 minutes, 100% B for 2 minutes, 100% B to 20% B:80% A in        0.5 minutes, 20% B:80% A for 3.5 minutes, Total run time 16        minutes with a flow rate of 1.0 mL/minute; 210-300 nM, 220 and        254 nM extracted and ELSD; Column Temp 30° C.; Mass Spec        Quadrupole, Electrospray, cone voltage 25V, +/−ion switching,        centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan        delay.        Method R:    -   Phenomenex Luna C18(2) 5 μM Column (150×4.6 mm) using gradient        elution with a mixture of (A) 10 mm ammonium acetate in water        and (B) 10 mm ammonium acetate in methanol (40% B:60% A to 100%        B in 10 minutes, 100% B for 2 minutes, 100% B to 40% B:60% A in        0.5 minutes, 40% B:60% A for 3.5 minutes, Total run time 16        minutes with a flow rate of 1.0 mL/minute; 210-300 nM, 220 and        254 nM extracted and ELSD; Column Temp 30° C.; Mass Spec        Quadrupole, Electrospray, cone voltage 25V, +/−ion switching,        centroid data, 100 to 900 Da, 0.6 sec scan, 0.4 sec inter scan        delay.

High Pressure Liquid Chromatography conditions for determination ofretention times (R_(T)) were as follows:—

Method A1:

-   -   YMC ODS-AQ (2×50 mm) column using gradient elution conditions        with mixtures of acetonitrile, water and formic acid as the        mobile phase [95/5/0.1% to 5/95/0.1%] and a flow rate of 0.4        mL/minute.        Method B1:    -   C18 Phenomenex Luna 5 μM (150×4.6 mm) column using gradient        elution with a mixtures of (A) acetonitrile containing 0.1%        formic acid and (B) water containing 0.1% formic acid as the        mobile phase (gradient: 0-2 minutes 10% A:90% B; 2-25 minutes        ramp up to 100% A; 25-32 minutes 100% A; 32-33 minutes 10%        A:90% B) with a flow rate of 1.0 ml/minute.        Method C1:    -   C18 Phenomenex Luna 5 μM (150×4.6 mm) column using gradient        elution with a mixture of (A) methanol and (B) water with 10 mM        ammonium acetate as the mobile phase (0-2 minutes 10% A:90% B;        2-25 minutes ramp up to 100% A; 25-32 minutes 100% A; 32-33        minutes 10% A:90% B) with a flow rate of 1.0 ml/minute.        Method D1:    -   C18 Phenomenex Luna 3 μM (150×4.6 mm) column using gradient        elution with a mixture of (A) acetonitrile containing 0.1%        formic acid and (B) water containing 0.1% formic acid with a        flow rate of 1.0 ml/minute        Method E1:    -   C18 Phenomenex Luna 3 μM (150×4.6 mm) column using gradient        elution with a mixture of (A) methanol and (B) water with 10 mM        ammonium acetate as the mobile phase (20% A:80% B to 100% A in        10 minutes; 100% A for 2 minutes; 100% Ato 20% A:80% B in 0.5        minutes; 20% A:80% B for 3.5 minutes) with a flow rate of 1.0        ml/minute.        Method F1:    -   C18 Phenomenex Luna 3 μM (150×4.6 mm) column using gradient        elution with a mixture of acetonitrile and water with 0.1%        formic acid.        Method G1:    -   C18 Phenomenex Luna 3 μM (150×4.6 mm) column using gradient        elution with a mixture of (A) methanol and (B) water with 10 mM        ammonium acetate as the mobile phase (5% A; 95% B to 60% A:40% B        in 10 minutes; 60% A:40% B for 2 minutes; 60% A:40% B to 5%        A:95% B in 0.5 minutes; 5% A:95% B for 3.5 minutes) with a flow        rate of 1.5 ml/minute.

Gas Chromatography-Mass Spectrometry (GC-MS) conditions fordetermination of retention times (R_(T)) and associated mass ions wereas follows:

Varian 3800 Gas Chromatograph with Chrompack 0.25 mm diameter fusedsilica 30 m column using a 20 minute elution with 25° C./minute gradientfrom 50 to 300° C. from time 1 to 11 minute; helium mobile phase with1.2 mL/minute flow rate; 3-8 μL injection volume with 50:50 injectionsplit ratio; Varian 2000R mass spectrometer with electron impactdetection for ions 40 to 650 m/z.

General method of LC-MS purification of examples 1 to 229: a WatersFraction Lynx system is used, and the separations were carried out on aWaters Symmetry column (C18, 5 μM, 19×50 mm, catalogue number186000210), eluting with a linear gradient of acetonitrile containing0.07% trifluoroacetic acid (v/v) in water containing 0.07%trifluoroacetic acid (v/v), gradient rising from 5% to 95% (v/v) ofacetonitrile/trifluoroacetic acid over 8 minutes, and then 2 minutes at95% acetonitrile/trifluoroacetic acid at a flow rate of 10 ml/minute.The products are injected in solution in dimethylsulfoxide, andcollected according to the detection of their molecular weight.

Compound names were generated using an auto-nom plug in for ISIS2.3 orISIS2.4.

EXAMPLE 1 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidbenzylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide maybe prepared in the following manner.

A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide is added,at a temperature in the region of 20° C., to a solution of 20 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid in 0.42 ml ofanhydrous dimethylformamide. After stirring at a temperature in theregion of 20° C. for one hour, 15.7 ml of benzylamine are added,followed by addition of 12.4 ml of N,N-diisopropylethylamine dissolvedin 0.32 ml of dimethylformamide. After 20 hours, at a temperature in theregion of 20° C., the reaction medium is concentrated under reducedpressure, at a temperature in the region of 40° C. The crude residueobtained is dissolved in DMSO and purified by preparative LC-MS. Thefractions containing the desired product are combined and concentratedunder reduced pressure at a temperature in the region of 40° C. 20 mg of21H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide arethus obtained in the form of a cream-coloured powder, thecharacteristics of which are as follows:

LC-MS retention time=2.86 minutes

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid may be preparedin the following manner: 1.3 g of sodium metabisulphite and 1.04 g of3,4-diaminobenzoic acid are added, at a temperature in the region of 20°C., to a solution of 1 g of 1H-indazole-3-carboxaldehyde in 10 ml ofdimethylformamide. The reaction mixture is refluxed for one hour andthen cooled to a temperature in the region of 20° C. and diluted withdichloromethane, and the mixture is filtered. The collected filtrate isconcentrated under reduced pressure. The brown lacquer obtained (340 mg)is purified by preparative LC-MS. 138.8 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid are thus obtainedin the form of a beige-coloured powder.

1H-Indazole-3-carboxaldehyde may be prepared in the following manner:

A solution of 2.27 g of (1H-indazol-3-yl)methanol in 220 ml of1,2-dimethoxyethane is added to 13.32 g of manganese dioxide. After onehour at a temperature in the region of 20° C., the reaction mixture isrefluxed for 15 minutes. After cooling to a temperature in the region of20° C., the reaction medium is filtered through a sinter funnel packedwith Celite. The collected filtrate is concentrated under reducedpressure at a temperature in the region of 40° C. 2.02 g of1H-indazole-3-carboxaldehyde are thus obtained in the form of a yellowpowder, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 7.40 ppm (triplet, 1H); 7.55 ppm (triplet,1H); 7.75 ppm (doublet, 1H); 8.18 ppm (doublet, 1H); 10.23 ppm (singlet,1H); 14.2 ppm (multiplet, 1H).

(1H-Indazol-3-yl)methanol may be prepared in the following manner:

3.2 g of lithium aluminium hydride are added portionwise to a solutionof 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran,cooled to a temperature in the region of 0° C. by an ice bath. After 4hours at a temperature in the region of 0° C., 1.6 g of lithiumaluminium hydride are added. After 2 hours at a temperature in theregion of 0° C., the reaction medium is treated successively with 6 mlof water and then 6 ml of aqueous 1N sodium hydroxide solution andfinally 18 ml of water. The reaction mixture is filtered through paperand the aqueous filtrate is then extracted with dichloromethane. Thecollected organic fractions are combined, dried over magnesium sulphateand concentrated under reduced pressure at a temperature in the regionof 40° C. 3.15 g of (1H-indazol-3-yl)methanol are obtained in the formof an off-white powder, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 4.80 ppm (doublet, 21); 5.25 ppm (triplet,1H); 7.15 ppm (triplet, 1H); 7.35 ppm (triplet, 1H); 7.51 ppm (doublet,1H); 7.87 ppm (doublet, 1H); 12.81 ppm (multiplet, 1H).

Methyl 3-indazolecarboxylate may be prepared in the following manner:

0.5 ml of concentrated sulphuric acid (95%) is added dropwise, at atemperature in the region of 20° C., to a solution of 9.13 g of3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for 20hours, the reaction medium is concentrated under reduced pressure at atemperature in the region of 40° C. The aqueous residue obtained isextracted with dichloromethane. The organic phases are combined, washedwith water until neutral, dried over magnesium sulphate and thenconcentrated under reduced pressure at a temperature in the region of40° C. The yellow powder obtained is washed with ethyl ether. A whitepowder is obtained. The filtrate is concentrated under reduced pressureuntil a yellow powder is obtained. This yellow powder is washed againwith ethyl ether until a white powder is obtained. The yellow filtrateis concentrated a third time under reduced pressure and the yellowpowder collected is itself also washed with ethyl ether. All thefractions of white powder are combined. 7.08 g of methyl3-indazolecarboxylate are thus obtained in the form of a white powder.

EXAMPLE 2 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-methylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide maybe prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 71.8 μl of a methylamine solution (2M in tetrahydrofuran), 14.8mg of expected product are obtained.

EXAMPLE 3 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-ethylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide maybe prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 19.4 ml of an ethylamine solution (33% in water) 14.8 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide areobtained.

EXAMPLE 4 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-isopropylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamidemay be prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 12.3 ml of isopropylamine, 16.5 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamideare obtained.

EXAMPLE 5 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-phenylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide maybe prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 13.1 ml of aniline, 14.1 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide areobtained in the form of a white powder.

EXAMPLE 6 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-phenethylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamidemay be prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 18 ml of phenethylamine, 17.7 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamideare obtained in the form of a white powder.

EXAMPLE 7 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-morpholinoamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamidemay be prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 12.5 ml of morpholine, 18.6 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamideare obtained in the form of a pale yellow powder.

EXAMPLE 8 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(N′-methyl-piperazino)amide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(N′-methyl-piperazino)amide may be prepared by following the procedurefor the preparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid N-benzylamide (Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 15.9 ml of N-methylpiperazine, 16.1 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(N′-methyl-piperazino)amide are obtained in the form of a yellow oil.

EXAMPLE 9 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-pyrrolidinoamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-pyrrolidinoamide may be prepared by following the procedure for thepreparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-benzylamide (Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 12 ml of pyrrolidine, 17.7 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-pyrrolidinoamide are obtained in the form of a pale yellow powder.

EXAMPLE 10 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(isobutyl)amide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(isobutyl)amidemay be prepared by following the procedure for the preparation of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzylamide(Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 14.6 ml of isobutylamine, 7.6 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(isobutyl)amideare obtained in the form of a pale yellow powder.

EXAMPLE 11 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(cyclohexylmethyl)amide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(cyclohexylmethyl)amide may be prepared by following the procedure forthe preparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid N-benzylamide (Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 18.7 ml of cyclohexylmethylamine, 16.1 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-cyclohexylmethyl)amide are obtained in the form of a white powder.

EXAMPLE 12 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(2-furfuryl)amide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(2-furfuryl)amide may be prepared by following the procedure for thepreparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-benzylamide (Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 13.3 ml of 2-furfurylamine, 14.8 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-(2-furfuryl)amide are obtained in the form of a white powder.

EXAMPLE 13 2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-benzyl-N-methylamide

2-(1H-Indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-benzyl-N-methylamide may be prepared by following the procedure forthe preparation of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid N-benzylamide (Example 1):

Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylicacid and 18.6 ml of N-methylbenzylamine, 7.3 mg of2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acidN-benzyl-N-methylamide are obtained in the form of a pale yellow powder.

EXAMPLE 14 Methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate

Methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate may beprepared in the following manner:

A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg ofmethyl 3,4-diaminobenzoate in 10 ml of nitrobenzene is maintained at atemperature in the region of 145° C. for 3 hours and 45 minutes. Aftercooling to a temperature in the region of 20° C., the reaction mixtureis purified on SPE (5 g of SCX phase, processing and washing withmethanol, extraction with a 2N ammoniacal methanol solution). Theammoniacal solution collected during the detachment is then concentratedunder reduced pressure at a temperature in the region of 40° C. 198.3 mgof an orange lacquer are obtained and are purified by preparative LC-MS.42.7 mg of methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate arethus obtained in the form of a beige-coloured powder, thecharacteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 3.95 ppm (singlet, 3H); 7.40 ppm (triplet,1H); 7.55 ppm (triplet, 1H); 7.75 ppm (doublet, 1H); 7.77 ppm (doublet,1H); 7.95 ppm (doublet, 1H); 8.57 ppm (doublet, 1H); 13.85 ppm(multiplet, 1H).

EXAMPLE 15 5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole

5,6-Dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole may be prepared byfollowing the procedure for the preparation of methyl2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate (Example 14):

Starting with 200 mg of 1H-indazole-3-carboxaldehyde and 177 mg of4,5-dimethyl-1,2-phenylenediamine in 10 ml of nitrobenzene, 15.9 mg of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole are obtained in theform of a dark red powder, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 2.60 ppm (singlet, 6H); 7.42 ppm (triplet,1H); 7.53 ppm (singlet, 2H); 7.58 ppm (triplet, 1H); 7.78 ppm (doublet,1H); 8.52 ppm (doublet, 1H); 14.05 ppm (multiplet, 1H).

5,6-Dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole may also be preparedaccording to the following procedure:

389 mg of sodium metabisulphite are added, at a temperature in theregion of 20° C., to a solution of 300 mg of1H-indazole-3-carboxaldehyde and 279 mg of4,5-dimethyl-1,2-phenylenediamine in 3 ml of dimethylformamide. Thereaction mixture is refluxed for 4 hours and then cooled to atemperature in the region of 20° C. and filtered through paper. Thecollected filtrate is concentrated under reduced pressure. The brownlacquer obtained (340 mg) is purified by preparative LC-MS. 138.8 mg of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole are thus obtained inthe form of a beige-coloured powder.

EXAMPLE 16 5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole

5-Methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole may be prepared byfollowing the procedure for the preparation of methyl2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate (Example 14):

Starting with 200 mg of 1H-indazole-3-carboxaldehyde and 274.4 mg of4-methoxy-1,2-phenylenediamine dihydrochloride in 10 ml of nitrobenzene,45.6 mg of 5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole are obtainedin the form of a light brown powder, the characteristics of which are asfollows:

¹H NMR (DMSO d6, 400 MHz): 3.90 ppm (singlet, 3H); 7.00 ppm (doublet,1H); 7.18 ppm (doublet, 1H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet,1H); 7.64 ppm (doublet, 1H); 7.73 ppm (doublet, 1H); 8.52 ppm (doublet,1H); 13.91 ppm (multiplet, 1H).

EXAMPLE 17 2-(1H-Indazol-3-yl)-3H-benzimidazole-4-carboxylic acid

2-(1H-Indazol-3-yl)-3H-benzimidazole-4-carboxylic acid may be preparedby following the procedure for the preparation of methyl2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate (Example 14):

Starting with 237 mg of 1H-indazole-3-carboxaldehyde and 305.5 mg of2,3-diaminobenzoic acid hydrochloride in 10 ml of nitrobenzene, 20.5 mgof 2-(1H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid are obtainedin the form of a beige-coloured powder, the characteristics of which areas follows:

1HNMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.42 ppm (triplet, 1H);7.55 ppm (triplet, 1H); 7.72 ppm (doublet, 1H); 7.90 ppm (doublet, 1H);8.02 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.68 ppm (multiplet,1H).

EXAMPLE 18 5-bromo-2-(1H-indazol-3-yl)-3H-benzimidazole

5-Bromo-2 (1H-indazol-3-yl)-3H-benzimidazole may be prepared byfollowing the procedure for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of4-bromo-1,2-phenylenediamine, and 836.5 mg of sodium metabisulphite in15 ml of dimethylformamide, and after purification by SPE (SCX phase,washing with methanol, extraction with 2N ammoniacal methanol) followedby a chromatography under pressure on silica, 939 mg of5-bromo-2-(1H-indazol-3-yl)-3H-benzimidazole are obtained in the form ofa brick-red powder.

EXAMPLE 19 2-(5-Ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylicacid

2-(5-Ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid may beobtained from2-(2-benzyl-5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acidby deprotection of the benzyl group in the presence of hydrogen and acatalyst such as palladium.

2-(2-Benzyl-5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acidmay be prepared by following the procedure for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde,and 17.7 mg of 3,4-diaminobenzoic acid hydrochloride in 1 ml ofnitrobenzene, and after purification by SPE (SCX phase, washing withmethanol, extraction with 2N ammoniacal methanol), 50.9 mg of2-(2-benzyl-5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acidare obtained in the form of a yellow lacquer.

2-Benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde may be prepared in thefollowing manner:

4 Å molecular sieves are added to a solution of 45.7 mg of(2-benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol in 0.5 ml ofdichloromethane, followed by addition of 43.1 mg of pyridiniumchlorochromate. After 20 hours at a temperature in the region of 20° C.,the reaction mixture is filtered through Celite. The insoluble materialformed is rinsed with ethyl acetate and then with dichloromethane. Thefiltrate is washed with water. After separation of the phases bysettling, the aqueous phase is re-extracted with dichloromethane. Theorganic phases are combined, dried over magnesium sulphate, filtered andthen concentrated under reduced pressure. 21.6 mg of2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde are thus obtained in theform of a brown lacquer, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.25 ppm (quartet,2H); 5.30 ppm (singlet, 2H); 6.30 ppm (singlet, 1H); 7.25-7.40 ppm(multiplet, 5H); 9.72 ppm (singlet, 1H).

(2-Benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol may be prepared in thefollowing manner:

11.1 mg of lithium aluminium hydride are added to a solution of 76 mg ofmethyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate in 0.75 ml oftetrahydrofuran, cooled to a temperature in the region of 0° C. by anice bath. After 3 hours at a temperature in the region of 0° C., 22.2 mgof lithium aluminium hydride are added and the reaction medium isallowed to warm to a temperature in the region of 20° C. After 30minutes at a temperature in the region of 20° C., 10 ml of ice-coldwater are added and the reaction mixture is then filtered throughCelite. After separation of the phases by settling, the aqueous phase isextracted with ethyl acetate. The organic phases are combined, driedover magnesium sulphate and concentrated under reduced pressure. 45.7 mgof (2-benzyl-5-ethoxy-2H-pyrazol-3-yl)methanol are thus obtained in theform of a brown lacquer, the characteristics of which are as follows:

¹HNMR(DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 4.15 ppm (quartet, 2H);4.30 ppm (doublet, 2H); 5.00 ppm (triplet, 1H); 5.08 ppm (singlet, 2H);5.70 ppm (singlet, 1H); 7.20-7.40 ppm (multiplet, 5H).

Methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate may be prepared inthe following manner:

5 mg of sodium iodide, 36 μl of bromoethane and 70 mg of potassiumcarbonate are added, at a temperature in the region of 20° C., to asolution of 100 mg of methyl2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in 1 ml of acetone. Thereaction mixture is refluxed for 9 hours, cooled to a temperature in theregion of 20° C. and filtered. The filtrate is concentrated underreduced pressure. 76 mg of methyl2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate are thus obtained in theform of a solid, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 1.35 ppm (triplet, 3H); 3.50 ppm (singlet,3H); 4.22 ppm (quartet, 2H); 5.22 ppm (singlet, 2H); 6.28 ppm (singlet,1H); 7.20-7.40 ppm (multiplet, 5H).

Methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate may be prepared inthe following manner:

1.72 ml of dimethylacetylene dicarboxylate are added, at a temperaturein the region of 20° C., to a solution of 2.73 g of benzylhydrazinedihydrochloride in 45 ml of glacial acetic acid. The reaction mixture isrefluxed for 3 hours, cooled to a temperature in the region of 20° C.and then concentrated under reduced pressure. After filtering off theinsoluble material formed, 252 mg of methyl2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate are collected in the formof a white powder, the characteristics of which are as follows:

¹H NMR (DMSO d6, 400 MHz): 3.76 ppm (singlet, 3H); 5.19 ppm (singlet,2H); 5.85 ppm (singlet, 1H); 7.25-7.45 ppm (multiplet, 5H); 11.69 ppm(multiplet, 1H).

The filtrate may be purified by flash chromatography on 400 g of 20-45μm silica (applied in a 25/75 ethyl acetate/cyclohexane mixture; eluant:25/75 and then 40/60 ethyl acetate/cyclohexane) to give an additionalbatch of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in the formof a white powder.

EXAMPLE 20 5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole

5,6-Dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole may beprepared by following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 53.3 mg of 5-methyl-2H-pyrazole-3-carboxaldehyde, 65.9 mgof 4,5-dimethyl-1,2-phenylenediamine, and 92 mg of sodiummetabisulphite, in 0.5 ml of ethanol and 1.5 ml of dimethylformamide,and after purification by SPE (SCX phase, washing with methanol,extraction with 2N ammoniacal methanol) followed by a chromatographyunder pressure on silica, 20.8 mg of5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole are obtainedin the form of a white powder.

5-Methyl-2H-pyrazole-3-carboxaldehyde may be prepared from commercialethyl 5-methyl-2H-pyrazole-3-carboxylate by following the proceduredescribed for the preparation of 1H-indazole-3-carboxaldehyde, startingwith methyl 3-indazolecarboxylate.

EXAMPLE 215,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole

5,6-Dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole may beprepared by following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde,12.4 mg of 4,5-dimethyl-1,2-phenylenediamine, and 17.3 mg of sodiummetabisulphite, in 0.2 ml of ethanol and 0.6 ml of dimethylformamide,and after purification by SPE (SCX phase, washing with methanol,extraction with 2N ammoniacal methanol) followed by a chromatographyunder pressure on silica and a purification by LC-MS,5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole isobtained in the form of a white powder.

5-Thiophen-2-yl-2H-pyrazole-3-carboxaldehyde may be prepared fromcommercial ethyl 5-thiophen-2-yl-2H-pyrazole-3-carboxylate by followingthe procedure described for the preparation of1H-indazole-3-carboxaldehyde starting with methyl 3-indazolecarboxylate.

EXAMPLE 22 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole

2-(4-Bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole may beprepared by following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 100 mg of commercial 4-bromo-2H-pyrazole-3-carboxaldehyde,77.8 mg of 4,5-dimethyl-1,2-phenylenediamine, and 108.6 mg of sodiummetabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, andafter purification by SPE (SCX phase, washing with methanol, extractionwith 2N ammoniacal methanol) followed by a chromatography under pressureon silica, 143.2 mg of2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole are obtainedin the form of a yellow foam.

EXAMPLE 23 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole

2-(5-Ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole may beprepared by following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 110 mg of4,5-dimethyl-1,2-phenylenediamine, and 153 mg of sodium metabisulphite,in 1 ml of ethanol and 3 ml of dimethylformamide, and after purificationby SPE (SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions100×25 mm, flow rate 20 m/min, elution gradient acetonitrile/0.07%TFA—water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol), 82 mg of2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole are obtainedin the form of a beige-coloured powder, the characteristics of which areas follows:

¹H NMR (DMSO d6, 300 MHz): 1.26 (t, J=7 Hz: 3H); 2.31 (s: 6H); 2.70(broad q, J=7 Hz: 2H); 6.60 (broad s: 1H); 7.22 (mult: 1H); 7.36 (mult:1H); 12.37 (mult: 1H); 12.92 (mult: 1H).

5-Ethyl-2H-pyrazole-3-carboxaldehyde may be prepared from ethyl5-ethyl-2H-pyrazole-3-carboxylate by following the procedure describedfor the preparation of 1H-indazole-3-carboxaldehyde starting with methyl3-indazolecarboxylate.

Ethyl 5-ethyl-2H-pyrazole-3-carboxylate may be prepared according to thegeneral procedure in the following reference: Kunio Seki et al., Chem.Pharm. Bull., 32(4), 1568-1577 (1984).

EXAMPLE 242-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole

2-(5-Ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole may beprepared by following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 134 mg of3,4-ethylenedioxy-1,2-phenylenediamine, and 153 mg of sodiummetabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, andafter purification by SPE (SCX phase, washing with methanol, extractionwith 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm, C18phase, dimensions 100×25 mm, flow rate 20 m/min, elution gradientacetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), anddesalification by SPE (SCX phase, washing with methanol, extraction with2N ammoniacal methanol), 60 mg of2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole areobtained in the form of a brown lacquer, the characteristics of whichare as follows:

¹H NMR (DMSO d6, 300 MHz): 1.27 (t, J=7 Hz: 3H); 2.70 (broad q, J=7 Hz:2H); from 4.20 to 4.45 (mt: 4H); 6.61 (broad s: 1H); 6.72 (d, J=8 Hz:1H); 6.88 (broad d, J=8 Hz: 1H); 12.50 (mult: 1H); 12.94 (mult: 1H).

EXAMPLE 25 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole

2-(5-Ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole may be preparedby following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg of4-methoxy-1,2-phenylenediamine, and 153 mg of sodium metabisulphite, in1 ml of ethanol and 3 ml of dimethylformamide, and after purification bySPE (SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07%TFA—water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol), 61 mg of2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole are obtained inthe form of a brown lacquer, the characteristics of which are asfollows:

¹H NMR (DMSO d6 with addition of a few drops of CD₃COOD, 300 MHz): 1.26(t, J=7 Hz: 31); 2.70 (q, J=7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1H); 6.81(dd, J=8.5 and 2.5 Hz: 1H); 7.03 (broad s: 1H); 7.42 (d, J=8.5 Hz: 1H).

EXAMPLE 26 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole

2-(5-Ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole may be preparedby following the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg of2,3-diaminophenol, and 153 mg of sodium metabisulphite, in 1 ml ofethanol and 3 ml of dimethylformamide, and after purification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol) followed by a reverse-phase HPLC (5 mm, C18 phase, dimensions:100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07%TFA—water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol), 16 mg of2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole are obtained inthe form of a brown lacquer, the characteristics of which are asfollows:

¹H NMR (DMSO d6 with addition of a few drops of CD₃COOD, 300 MHz): 1.26(t, J=7 Hz: 3H); 2.70 (q, J=7 Hz: 2H); 6.55 (t, J=4.5 Hz: 1H); 6.66 (s:1H); 6.96 (broad d, J=4.5 Hz: 2H).

EXAMPLE 27 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole

2-(5-Ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole may be prepared byfollowing the procedure described for the preparation of5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole (Example 15):

Starting with 20 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 30 mg of4-bromo-1,2-phenylenediamine and 30 mg of sodium metabisulphite, in 1 mlof ethanol and 2 ml of dimethylformamide, and after purification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions:100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07%TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE(SCX phase, washing with methanol, extraction with 2N ammoniacalmethanol), 21 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazoleare obtained in the form of a yellow powder, the characteristics ofwhich are as follows:

¹H NMR (DMSO d6, 300 MHz): 1.28 (t, J=7 Hz: 3H); 2.71 (q, J=7 Hz: 2H);6.67 (s: 1H); 7.30 (dd, J=8.5 and 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712(broad s: 1H); from 12.5 to 13.5 (broad mult: 2H).

The products of formula (I) of the present application can also beprepared according to the following process:

The products of Examples 97 to 145 of the present applicationrepresented in the TABLE 3 below can be prepared according to theschemes indicated above and in particular according to the proceduresindicated below.

EXAMPLE 97 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole Step 1:Synthesis of 3-(6-bromo-1H-benzimidazol-2-yl)-2H-indazole (otherpreparation of example 18)

4.25 g of 1-hydroxybenzotriazole and 4.3 g of calcium sulphate are addedat ambient temperature to a solution of 4.6 g of indazole-3-carboxylicacid in 50 ml of dimethylformamide. The reaction mixture is cooled toapproximately 0° C. and then 4.9 ml of N,N-diisopropylcarbodiimide areslowly added. After stirring for 2 hours at ambient temperature, 5.9 gof 4-bromo-o-phenylenediamine are added. After stirring for 60 hours atambient temperature, the reaction mixture is concentrated to drynessunder reduced pressure. The brown oil obtained is taken up in 50 ml ofwater and extracted 3 times with 50 ml of ethyl acetate. The organicphases are combined, dried over magnesium sulphate and then concentratedto dryness under reduced pressure. 18 g of a brown oil are thusobtained, which oil is taken up in 100 ml of a 20% solution ofhydrochloric acid in ethanol. The mixture is brought to reflux for 4hours and then concentrated to dryness, the brown oil obtained is takenup in 20 ml of water, and an aqueous ammonia solution is run in until apH of the mixture of about 8-9 is obtained. The aqueous phase is thenextracted 3 times with 30 ml of ethyl acetate and the organic phases arecombined, dried over magnesium sulphate and concentrated to drynessunder reduced pressure. After purification by chromatography underpressure on silica (eluent water/acetonitrile), 5 g of3-(6-bromo-1H-benzimidazol-2-yl)-2H-indazole are thus obtained.

IR spectrum (KBr): characteristic bands at 1621, 1570, 1441, 1344, 1324,1273, 1239, 1135, 1042, 914, 804, 774 and 746 cm⁻¹

Step 2: Synthesis of1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone

5 g of 3-(6-bromo-1H-benzimidazol-2-yl)-2H-indazole are charged to asolution of 40 ml of acetic anhydride and 40 ml of pyridine. The mixtureis brought to reflux for 4 hours and then concentrated to dryness afterreturning to ambient temperature. The brown solid obtained is taken upin 50 ml of ethyl acetate and washed with 50 ml of a saturated sodiumhydrogencarbonate solution until a pH of 7-8 is obtained. The organicphase is dried over magnesium sulphate, filtered and then concentratedto dryness under reduced pressure. The light brown solid obtained istriturated in 20 ml of ethyl acetate and then filtered off on a sinteredglass funnel. 1.5 g of the compound1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone arethus obtained. A second crop is obtained by chromatographing thefiltrate obtained above under pressure on silica (eluentcyclohexane/ethyl acetate), i.e. 1.3 g of the same compound.

Characteristics of the compound:

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm).

The mixture of the two positional isomers in the proportions 50/50 isobserved.

2.61 and 2.62 (2 s, 3H in all); 2.80 (s, 3H); 7.62 (broad t, J=7.5 Hz,1H); 7.68 and 7.71 (2 dd, J=9 and 2 Hz, 1H in all); 7.80 (ddd, J=8.5,7.5 and 0.5 Hz, 1H); 7.91 and 8.01 (2 d, J=9 Hz, 1H); 8.18 and 8.20 (2d, J=2 Hz, 1H in all); 8.27 and 8.30 (2 d, J=7.5 Hz, 1H in all); 8.46(d, J=8.5 Hz, 1H)

IR spectrum (KBr): characteristic bands at 1727, 1610, 1450, 1405, 1374,1326, 1290, 1198, 1176, 964 and 760 cm⁻¹

Step 3: Synthesis of 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole

40 mg of sodium carbonate, 7 mg ofdihydrogendichlorobis(di-tert-butylphosphonite-κP)palladate(2-)(POPd[0]) and 46 mg of phenylboronic acid are added under an argonatmosphere to a solution of 50 mg of1-[2-(1-acetyl-1H-indazol-3-yl)-5-bromobenzimidazol-1-yl]ethanone in 800μl of anhydrous tetrahydrofuran. The reaction mixture is brought toreflux for 3 hours and then cooled to ambient temperature. The mixtureis then diluted with 3 ml of ethyl acetate and then washed with 2 times2 ml of water. The organic phase is dried over magnesium sulphate andthen concentrated to dryness under reduced pressure. 48 mg of a brownsolid are obtained, which solid is dissolved in 500 μl oftetrahydrofuran, to which 500 μl of diethylamine are added. The reactionmixture is heated at 60° C. for 4 hours and then allowed to return toambient temperature. The mixture is then concentrated to dryness andthen the brown solid obtained is purified by LC-MS to produce 12.5 mg of3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole (6); analytical retentiontime 3.10, MS 311 [M+H]⁺.

The products of formula (I) of the present application and in particularexamples 98 to 145 can be prepared according to the following process:

The synthesis of examples 98 to 145 is carried out in a similar way tothe synthesis of 3-(6-phenyl-1H-benzimidazol-2-yl)-2H-indazole (example97) but replacing phenylboronic acid with boronic acids of formulaRB(OH)₂.

Products of formula (I) of the present application which constituteExamples 28 to 96 and 146 to 180 of the present application arerepresented in Table 3: these products can be prepared according to theschemes indicated above and in particular as indicated above for theproduct of Example 1. TABLE 3 MS Example Molecular Characteristic timenumber STRUCTURE RNH₂ or RB(OH)₂ Formula MW Method (minutes)Nomenclature 28

MFCD00013005 C22H18N6O3S 446.49 447 [M + H⁺ 2.77 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2,4- dichloro-benzylamide 29

MFCD00008221 C20H21N5O2 363.42 364 [M + H⁺ 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (3- ethoxy-propyl)-amide 30

chemistry 3

MFCD00047931 C22H16NrN5O 446.31 447 [M + H⁺ 3.35 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- bromo-benzylamide 31

MFCD000216491 C23H19N5O3S 445.50 446 [M + H]⁺ 2.81 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- methanesulfonyl- benzylamide 32

MFCD00004048 C26H19N5O 417.47 418 [M + H]⁺ 3.38 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (naphthalen-1- ylmethyl)-amide 33

chemistry 6

MFCD00010220 C23H16F3N5O 435.41 436 [M + H]⁺ 3.41 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- trifluoromethyl- benzylamide 34

chemistry 7

MFCD00005460 C20H15N5OS 373.44 374 [M + H]⁺ 3.01 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (thiophen-2- ylmethyl)-amide 35

MFCD00012862 C24H22N6O 410.48 411 [M + H]⁺ 2.49 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- dimethylamino- benzylamide 36

MFCD01076207 C26H30N6O3 474.56 475 [M + H]⁺ 3.31 4-({[2-(1H-Indazol-3-yl)-1H- benzoimidazole-5- carbonyl]-amino}- methyl)-piperidine-1-carboxylic acid tert- butyl ester 37

MFCD00012863 C22H16N6O3 412.41 413 [M + H]⁺ 3.14 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- nitro-benzylamide 38

MFCD00006412 C21H16N6O 368.40 369 [M + H]⁺ 2.39 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (pyridin-3-ylmethyl)- amide 39

chemistry 12

MFCD01026119 C22H16BrN5O 446.31 447 [M + H]⁺ 3.36 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- bromo-benzylamide 40

chemistry 16

MFCD00008115 C23H19N5O2 397.44 398 [M + H]⁺ 3.1 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- methoxy- benzylamide 41

chemistry 18

MFCD00005840 C23H17N5O3 411.42 412 [M + H]⁺ 3.07 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide 42

chemistry 19

MFCD00176440 C24H17N5OS 423.50 424 [M + H]⁺ 3.42 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide 43

chemistry 20

MFCD02055709 C21H19N7O 385.43 386 [M + H]⁺ 2.59 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl)- amide 44

MFCD00085176 C23H16F3N5O2 451.41 452 [M + H]⁺ 3.44 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carobyxlic acid 2- trifluoromethoxy- benzylamide 45

MFCD00008112 C23H19N5O 381.44 382 [M + H]⁺ 3.21 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- methyl-benzylamide 46

MFCD02093988 C21H17N5OS 387.46 388 [M + H]⁺ 3.16 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (3- methyl-thiophen-2-ylmethyl)-amide 47

MFCD00010297 C23H16F3N5O 435.41 436 [M + H]⁺ 3.38 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- trifluoromethyl- benzylamide 48

MFCD01310836 C28H21N5O2 459.51 460 [M + H]⁺ 3.56 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- phenoxy- benzylamide 49

MFCD00061267 C23H16F3N5O2 451.41 452 [M + H]⁺ 3.46 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- trifluoromethoxy- benzylamide 50

MFCD00008220 C21H23N5O2 377.45 378 [M + H]⁺ 2.94 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (3- isopropoxy-propyl)- amide 51

chemistry 29

MFCD02090924 C20H17N7O 371.40 372 [M + H]⁺ 2.56 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic aicd (1- methyl-1H-pyrazol-4-ylmethyl)-amide 52

MFCD00025580 C25H23N5O 409.49 410 [M + H]⁺ 3.51 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- isopropyl- benzylamide 53

MFCD02677701 C22H19N5O2 385.43 386 [M + H]⁺ 3.19 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl)-amide 54

MFCD00965305 C24H17N5OS 423.50 424 [M + H]⁺ 3.38 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (benzo[b]thiophen-2-ylmethyl)-amide 55 ch

MFCD00277760 C26H24N6O3 468.52 469 [M + H]⁺ 2.92 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid [3- (3-acetylamino-phenoxy)-propyl]- amide 56

MFCD00673153 C21H15ClN6O 402.84 403 [M + H]⁺ 2.92 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (6- chloro-pyridin-3-ylmethyl)-amide 57

38

MFCD00110111 C24H17N5OS2 455.56 456 [M + H]⁺ 3.47 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid ([2,2′]bithiophenyl-5-ylmethyl)-amide 58

chemistry 40

MFCD00728869 C24H19N5O2 409.45 410 [M + H]⁺ 3.07 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (2,3-dihydro- benzofuran-5-ylmethyl)-amide 59

chemistry 41

MFCD01861472 C23H16N6O 392.42 393 [M + H]⁺ 3.03 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- cyano-benzylamide 60

chemistry 42

MFCD02677713 C24H16ClN5OS 457.94 458 [M + H]⁺ 3.55 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (5-chloro- benzo[b]thiophen-3-ylmethyl)-amide 61

MFCD00008117 C23H16F3N5O 435.41 436 [M + H]⁺ 3.41 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- trifluoromethyl- benzylamide 62

MFCD00831039 C23H19N5OS 413.50 414 [M + H]⁺ 3.26 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- methylsulfanyl- benzylamide 63

chemistry 46

MFCD00176440 C24H17N5OS 423.50 424 [M + H]⁺ 3.38 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide 64

MFCD02179435 C21H21N5O2 375.43 376 [M + H]⁺ 2.65 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide 65

chemistry 48

MFCD00203985 C24H19N5O3 425.45 426 [M + H]⁺ 3.28 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (2,3-dihydro- benzo[1,4]dioxin-2-ylmethyl)-amide 66

chemistry 49

MFCD02681983 C20H15N5O2 357.37 358 [M + H]⁺ 2.92 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (furan-3-ylmethyl)- amide 67

chemistry 50

MFCD00136280 C22H16N6O3 412.41 413 [M + H]⁺ 3.14 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- nitro-benzylamide 68

chemistry 51

MFCD01529872 C20H15N5OS 373.44 374 [M + H]⁺ 3.03 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (thiophen-3- ylmethyl)-amide 69

chemistry 52

MFCD00040753 C24H21N5O 395.47 396 [M + H]⁺ 3.37 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3,5-dimethyl- benzylamide 70

chemistry 53

MFCD00457746 C24H19N7O 421.46 422 [M + H]⁺ 2.61 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (1-methyl-1H- benzoimidazol-2-ylmethyl)-amide 71

chemistry 54

MFCD00008118 C23H19N5O 381.44 382 [M + H]⁺ 3.24 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- methyl-benzylamide 72

chemistry 55

MFCD00040752 C22H16ClN5O 401.86 402 [M + H]⁺ 3.29 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- chloro-benzylamide 73

MFCD00013005 C22H18N6O3S 446.49 447 [M + H]⁺ 3.07 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 4- sulfamoyl- benzylamide 74

chemistry 57

MFCD00008221 C20H21N5O2 363.42 364 [M + H]⁺ 3.45 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (3- ethoxy-propyl)-amide 75

chemistry 58

MFCD00047931 C22H16BrN5O 446.31 447 [M + H]⁺ 4.38 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 4- bromo-benzylamide 76

MFCD00004048 C26H19N5O 417.47 418 [M + H]⁺ 4.4 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (naphthalen-1- ylmethyl)-amide 77

MFCD00005460 C20H15N5OS 373.44 374 [M + H]⁺ 3.93 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (thiophen-2- ylmethyl)-amide 78

MFCD00012862 C24H22N6O 410.48 411 [M + H]⁺ 2.93 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 4- dimethylamino- benzylamide 79

MFCD00012863 C22H16N6O3 412.41 413 [M + H]⁺ 3.87 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 4- nitro-benzylamide 80

MFCD00006412 C21H16N6O 368.40 369 [M + H]⁺ 2.4 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (pyridin-3-ylmethyl)- amide 81

chemistry 65

MFCD01026119 C22H16BrN5O 446.31 447 [M + H]⁺ 4.18 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3- bromo-benzylamide 82

MFCD00008115 C23H19N5O2 397.44 398 [M + H]⁺ 3.95 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3- methoxy- benzylamide 83

MFCD00176440 C24H17N5OS 423.50 424 [M + H]⁺ 4.68 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide 84

MFCD01310836 C28H21N5O2 459.51 460 [M + H]⁺ 4.55 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 4-phenoxy- benzylamide 85

MFCD00061267 C23H16F3N5O2 451.41 452 [M + H]⁺ 4.43 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3- trifluoromethoxy- benzylamide 86

MFCD00673153 C21H15ClN6O 402.84 403 [M + H]⁺ 3.9 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (6- chloro-pyridin-3-ylmethyl)-amide 87

MFCD00728869 C24H19N5O2 409.45 410 [M + H]⁺ 3.9 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (2,3-dihydro- benzofurna-5-ylmethyl)-amide 88

MFCD00008117 C23H16F3N5O 435.41 436 [M + H]⁺ 4.3 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3- trifluoromethyl- benzylamide 89

chemistry 73

MFCD00831039 C23H19N5OS 413.50 414 [M + H]⁺ 3.98 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 2- methylsulfanyl- benzylamide 90

MFCD02681983 C20H15N5O2 357.37 358 [M + H]⁺ 3.68 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid (furan-3-ylmethyl)- amide 91

chemistry 75

MFCD00136280 C22H16N6O3 412.41 413 [M + H]⁺ 3.95 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 2- nitro-benzylamide 92

MFCD00040753 C24H21N5O 395.47 396 [M + H]⁺ 4.45 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3,5-dimethyl- benzylamide 93

MFCD00040752 C22H16ClN5O 401.86 402 [M + H]⁺ 5.03 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid 3- chloro-benzylamide 94

MFCD00007629 C21H15N5O 353.38 354 [M + H]⁺ 4.27 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid phenylamide 95

MFCD00008106 C22H17N5O 367.41 368 [M + H]⁺ 3.94 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid benzylamide 96

MFCD00008184 C23H19N5O 381.44 382 [M + H]⁺ 4.01 2-(1H-Indazol-3-yl)-3H-benzoimidazole- 4-carboxylic acid phenethyl-amide 97

MFCD00002103 C20H14N4 310.36 311 [M + H]+ 3.14 3-(6-Phenyl-1H-benzoimidazol-2- yl)-2H-indazole 98

chemistry 124

MFCD00013930 C20H12Cl2N4 379.25 379 [M + H]+ 3.63 3-[6-(2,4-Dichloro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 99

chemistry 125

MFCD00019722 C24H16N4 360.42 361 [M + H]+ 3.51 3-(6-Naphthalen-1-yl-1H-benzoimidazol- 2-yl)-2H-indazole 100

chemistry 126

MFCD00039136 C20H13FN4 328.35 329 [M + H]+ 3.21 3-[6-(4-Fluoro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 101

MFCD00039137 C20H13ClN4 344.805 345 [M + H+ 3.44 3-[6-(4-Chloro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 102

chemistry 128

MFCD00039139 C21H16N4O 340.386 341 [M + H]+ 3.14 3-[6-(4-Methoxy-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 103

chemistry 129

MFCD00051800 C20H12ClFN4 362.795 362 [M + H]+ 3.51 3-[6-(3-Chloro-4-fluoro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 104

chemistry 130

MFCD00051935 C20H12Cl2N4 379.25 [378-380[ [M + H]+ 3.813-[6-(3,5-Dichloro- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 105

chemistry 132

MFCD00093039 C26H16N4S2 448.57 449 [M + H]+ 3.91 3-(6-Thianthren-1-yl-1H-benzoimidazol-2- yl)-2H-indazole 106

chemistry 133

MFCD00093311 C26H18N4 386.45 387 [M + H]+ 3.78 3-(6-Biphenyl-4-yl-1H-benzoimidazol-2- yl)-2H-indazole 107

chemistry 137

MFCD00039138 C21H16N4 324.387 324 [M] 3.38 3-(6-p-Tolyl-1H-benzoimidazol-2-yl)- 2H-indazole 108

chemistry 138

MFCD00040198 C21H16N4 324.387 324 [M + H]+ 3-(6-m-Tolyl-1H-benzoimidazol-2-yl)- 2H-indazole 109

chemistry 139

MFCD00093526 C21H16N4 324.387 325 [M + H]+ 3-(6-o-Tolyl-1H-benzoimidazol-2-yl)- 2H-indazole 110

chemistry 140

MFCD00151851 C18H12N4S 316.386 317 [M + H]+ 3-(6-Thiophen-3-yl-1H-benzoimidazol-2-yl yl)-2H-indazole 111

chemistry 141

MFCD00151854 C21H13F3N4 378.357 379 [M + H]+ 3.65 3-[6-(3-Trifluoromethyl- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 112

chemistry 142

MFCD00151855 C21H13F3N4 378.357 379 [M + H]+ 3.68 3-[6-(4-Trifluoromethyl- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 113

chemistry 143

MFCD00161354 C20H13ClN4 344.805 345 [M + H]+ 3.55 3-[6-(3-Chloro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 114

chemistry 144

MFCD00161359 C21H16N4O 340.386 341 [M + H]+ 3.41 3-[6-(3-Methoxy-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 115

chemistry 145

MFCD00185689 C22H18N4 338.414 339 [M + H]+ 3.39 3-[6-(3,5-Dimethyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 116

chemistry 146

MFCD01009694 C22H18N4 338.414 339 [M + H]+ 3.55 3-[6-(3,4-Dimethyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 117

chemistry 147

MFCD01009695 C21H14N4O2 354.369 354 [M] 3.18 3-(6- Benzo[1,3]dioxol-5-yl-1H- benzoimidazol- 2-yl)-2H-indazole 118

chemistry 148

MFCD01009697 C24H22N4 366.468 367 [M + H]+ 3.95 3-[6-(4-tert-Butyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 119

chemistry 149

MFCD01074553 C20H20N4 316.408 317 [M + H]+ 3.72 3-(6-Hex-1-enyl-1H-benzoimidazol-2-yl)- 2H-indazole 120

chemistry 150

MFCD01074574 C22H18N4O2 370.412 371 [M + H]+ 3.00 3-[6-(3,4-Dimethoxy-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 121

chemistry 152

MFCD01074603 C20H14N4O 326.359 327 [M + H]+ 2.92 3-[2-(2H-Iindazol-3-yl)-3H- benzoimidazol-5-yl]- phenol 122

chemistry 153

MFCD01074628 C20H14N4O 326.359 327 [M + H]+ 2.84 4-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenol 123

chemistry 154

MFCD01074646 C20H12Cl2N4 379.25 378 [M + H]+ 3.82 3-[6-(3,4-Dichloro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 124

chemistry 157

MFCD01074648 C21H13F3N4O 394.356 395 [M + H]+ 3.72 3-[6-(4-Trifluoromethoxy- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 125

chemistry 159

MFCD01074667 C22H16N4O 352.397 353 [M + H]+ 3.08 1-{4-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenyl}-ethanone 126

chemistry 160

MFCD01075674 C22H14N4S 366.446 367 [M + H]+ 3.82 3-(6-Benzo[b]thiophen-2- yl-1H-benzoimidazol- 2-yl)-2H-indazole 127

chemistry 161

MFCD01075676 C23H20N4O3 400.438 401 [M + H]+ 3.02 3-[6-(3,4,5-Trimethoxy-phenyl)- 1H-benzoimidazol-2- yl]-2H-indazole 128

chemistry 162

MFCD01075681 C20H14N4OS 358.423 359 [M + H]+ 3.09 1-{5-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- thiophen-2-yl}- ethanone 129

chemistry 163

MFCD01074678 C22H16N4O 352.397 353 [M + H]+ 3.05 1-{3-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenyl}-ethanone 130

MFCD01075705 C27H20N4O 416.484 417 [M + H]+ 3.75 3-[6-(4-Benzyloxy-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 131

chemistry 165

MFCD01075707 C26H17FN4 404.448 405 [M + H]+ 4.02 3-[6-(2-Fluoro-biphenyl-4-yl)-1H- benzoimidazol-2-yl]- 2H-indazole 132

chemistry 167

MFCD01114669 C22H14N4S 366.446 367 [M + H]+ 3.55 3-(6-Benzo[b]thiophen-3- yl-1H-benzoimidazol- 2-yl)-2H-indazole 133

chemistry 168

MFCD01317846 C21H16N4O 340.386 341 [M + H]+ 2.79 {3-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenyl}-methanol 134

chemistry 171

MFCD01318146 C22H18N4S 370.478 371 [M + H]+ 3.62 3-[6-(4-Ethylsulfanyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 135

chemistry 176

MFCD01318998 C20H12F2N4 346.34 347 [M + H]+ 3.29 3-[6-(2,4-Difluoro-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 136

chemistry 178

MFCD01320697 C21H13F3N4O 394.356 395 [M + H]+ 3.66 3-[6-(3-trifluoromethoxy- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 137

chemistry 183

MFCD02093072 C21H15FN4 342.377 343 [M + H]+ 3.36 3-[6-(4-Fluoro-2-methyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 138

chemistry 184

MFCD02093725 C22H15FN4 354.388 355 [M + H]+ 3.49 3-{6-[2-(4-Fluoro-phenyl)-vinyl]-1H- benzoimidazol-2-yl}- 2H-indazole 139

chemistry 185

MFCD02093767 C22H15ClN4 370.843 371 [M + H]+ 3.76 3-{6-[2-(4-Chloro-phenyl)-vinyl]-1H- benzoimidazol-2-yl}- 2H-indazole 140

chemistry 188

MFCD01318119 C23H18N4O2 382.423 383 [M + H]+ 3.03 3-{4-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenyl}-propionic acid 141

chemistry 190

MFCD00792672 C21H16N4O 340.386 341 [M + H]+ 2.72 {4-[2-(2H-Indazol-3-yl)-3H- benzoimidazol-5-yl]- phenyl}-methanol 142

chemistry 191

MFCD00799544 C18H12N4O 300.321 301 [M + H]+ 3.02 3-(6-Furan-2-yl-1H-benzoimidazol-2-yl)- 2H-indazole 143

MFCD02093063 C27H20N4O 416.484 417 [M + H]+ 3.93 3-[6-(3-Benzyloxy-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 144

chemistry 194

MFCD01074614 C23H20N4 352.441 353 [M + H]+ 3.88 3-[6-(4-Isopropyl-phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 145

chemistry 195

MFCD01630820 C21H16N4O2S 388.449 389 [M + H]+ 3.03 3-[6-(4-Methanesulfonyl- phenyl)-1H- benzoimidazol-2-yl]- 2H-indazole 146

chemistry 84

MFCD00223987 C22H17N5O4 415.409 415 ,[M] 2.31 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide 147

chemistry 85

MFCD01861391 C24H20N6O2 424.464 424 ,[M] 2.58 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- acetylamino- benzylamide 148

chemistry 88 H₂N—MFCD00008104 C16H13N5O 291.314 291 ,[M] 2.222-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid methylamide149

chemistry 89

MFCD00008082 C18H17N5O 319.368 319 ,[M] 2.63 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid isopropylamide 150

chemistry 90

MFCD00005972 C19H17N5O2 347.378 347 ,[M] 2.23 [2-(1H-Indazol-3-yl)-1H-benzoimidazol-5- yl]-morpholin-4-yl- methanone 151

MFCD00005966 C20H20N6O 360.421 361 [M + H]⁺ 1.94 [2-(1H-Indazol-3-yl)-1H-benzoimidazol-5- yl]-(4-methyl- piperazin-1-yl)- methanone 152

chemistry 96

MFCD00008289 C23H19N5O 381.439 381 ,[M] 3.45 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid benzyl-methyl-amide 153

chemistry 97

MFCD00012858 C22H16N6O3 412.409 412 ,[M] 3.32 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3- nitro-benzylamide 154

chemistry 98

MFCD00008107 C22H16FN5O 385.402 385 ,[M] 2.96 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- fluoro-benzylamide 155

chemistry 99

MFCD00010142 C22H15F2N5O 403.392 403 ,[M] 3.26 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2,4- difluoro-benzylamide 156

chemistry 100

MFCD00010144 C22H15F2N5O 403.392 403 ,[M] 2.93 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2,6- difluoro-benzylamide 157

chemistry 101

MFCD00143266 C22H15BrFN5O 464.303 464 ,[M] 3.34 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- bromo-2-fluoro- benzylamide 158

chemistry 102

MFCD00143286 C22H15ClFN5O 419.847 419 ,[M] 3.21 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- chloro-2-fluoro- benzylamide 159

chemistry 103

MFCD00153076 C22H15NrFN5O 464.303 464 ,[M] 3.31 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- bromo-2-fluoro- benzylamide 160

chemistry 104

MFCD00010145 C22H15F2N5O 403.392 403 ,[M] 3.64 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3,4- difluoro-benzylamide 161

chemistry 105

MFCD00236318 C22H14F3N5O 421.382 421 ,[M] 3.35 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 3,4,5-trifluoro- benzylamide 162

chemistry 107

MFCD02089424 C28H20ClN5O 477.955 477 ,[M] 3.89 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (4′- chloro-biphenyl-4-ylmethyl)-amide 163

chemistry 108

MFCD02089425 C28H19Cl2N5O 512.4 512 ,[M] 4.36 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (3′,5′-dichloro-biphenyl-4-ylmethyl)- amide 164

chemistry 109

MFCD02089427 C28H20FN5O 461.5 461 ,[M] 3.6 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (4′- fluoro-biphenyl-4-ylmethyl)-amide 165

chemistry 110

MFCD01566531 C22H16FN5O 385.402 385 ,[M] 2.94 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2- fluoro-benzylamide 166

chemistry 111

MFCD01631410 C23H17F2N5O 417.419 417 ,[M ] 3.14 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2,6- difluor-3-methyl- benzylamide167

chemistry 112

MFCD00008109 C22H15Cl2N5O 436.302 436 ,[M] 3.48 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 2,4- dichloro-benzylamide 168

chemistry 113

MFCD00008121 C22H16ClN5O 401.857 401 ,[M] 3.73 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- chloro-benzylamide 169

chemistry 114

MFCD00047932 C23H18ClN5O 415.884 385 ,[M] 3.52 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- chloro-2-methyl- benzylamide 170

chemistry 115

MFCD00008120 C22H16FN5O 385.402 385 ,[M] 3.09 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid 4- fluoro-benzylamide 171

chemistry 116

MFCD02089431 C28H20ClN5O 477.955 477 ,[M] 3.9 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (2′- chloro-biphenyl-4-ylmethyl)-amide 172

chemistry 117

MFCD01862649 C22H15F3N6O 436.397 436 ,[M] 2.93 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (6- trifluoromethyl-pyridin-3-ylmethyl)- amide 173

chemistry 118

MFCD02681984 C25H18N6OS 450.524 450 ,[M] 2.67 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (5- pyridin-2-yl-thiophen-2-ylmethyl)-amide 174

chemistry 119

MFCD00009819 C21H19N7O 385.431 385 ,[M] 2.11 2-(1H-Indazol-3-yl)-1H-benzoimidazole- 5-carboxylic acid (3- imidazol-1-yl-propyl)- amide175

MFCD00075265 C24H26N6O3 446.511 447 [M + H]⁺ 3.11 4-[2-(1H-Indazol-3-yl)-1H- benzoimidazole-5- carbonyl]-piperazine- 1-carboxylic acidtert-butyl ester 176

chemistry 121

438 [M + H]⁺ 2-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid(2,6-difluoro-4- chloro-benzyl)amide 177

chemistry 122

437 [M + H]⁺ 2-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid(2,4-dichloro-6- fluoro-benzyl)amide 178

chemistry

420 [M + H]⁺ 2-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid(3- fluoro-4-chloro- benzyl)amide 179

chemistry 124

434 [M + H]⁺ 2-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid(2- fluoro-4-chloro-6- methyl-benzyl)amide 180

chemistry 125

399 [M + H]⁺ 2-(1H-Indazol-3-yl)- 1H-benzoimidazole- 5-carboxylic acid(6- methoxy-pyridin-3- ylmethyl)-amide

The products of formula (I) of the present application can also beprepared according to the following process:

In the above scheme, the values of Z3 and Z4 are chosen from the valuesof R2 and R3 as defined above and the values of Z1 and —OZ2 are chosenfrom the values of X1, X2 or X3 with R1 representing a pyrazole radical,

When Z1, Z3 and Z4 represent a hydrogen atom, it is possible inparticular to prepare products of formula (I) of the present applicationaccording to the following synthesis scheme:

Products of formula (I) of the present application which constituteExamples 181 to 228 of the present application are represented in thetable 4 hereinbelow: these products can be prepared according to theschemes indicated above and in particular the product of Example 181 canbe prepared according to the procedure indicated below. The products ofExamples 182 to 228 can be prepared like the product of Example 181.

EXAMPLE 181 2-[5-(benzyloxy)-2H-pyrazol-3-yl-1H-benzoimidazole

Step 1: the cyclization is performed as in: Chem. Pharm. Bull., 31(4),1228-1234 (1983); J. Org. Chem., 47(2), 214-221 (1982).

Step 2: To the crude ester 1.015 g in 50 ml of MeOH, was added 5.5 ml of6N NaOH and the mixture is heated to reflux during 2 h. Afterevaporation of most of the methanol, the medium is cooled and conc. HClis carefully added until pH=2. After further evaporation to dryness, thesolid is triturated three times with 30 ml of MeOH/AcOEt 1/1 and thefiltrate evaporated to give 0.875 g of light brown solid afterdesiccation.

LC-MS: [gradient acetonitrile/water 0.1% HCOOH; Xterra RP18 2.1×50 mm]retention time 0.53 minutes, MH+=129, 95% pure

Step 3: To 3.5 g of PPA (polyphosphoric acid) were added 0.701 g of1,2-phenylenediamine and 0.87 g of the step 2 acid. The mixture isheated to 150° C. during 1.5 h. After cooling, conc NH4OH was addeduntil pH=3. The green precipitate is filtered, washed with water andthen with acetone. After one night drying under vacuum at 50° C., 2.1 gof solid remains containing around 50% of mineral salts.

MS: EI M+=200.

Step 4: Ex. 181: To 80 mg of the step 3 solid in 4 ml of NMP were addedcaesium carbonate 137 mg and benzyl bromide 72 mg. After 2 h the mixtureis hydrolysed with saturated KH2PO4 and extracted with AcOEt. Afterevaporation, the crude mixture was submitted to preparative LC-MS togive 8 mg of pure compound:

LC-MS: [gradient acetonitrile/water 0.1% HCOOH; Xterra RP18 2.1×50 mm]retention time 3.17 minutes, MH+=291.97% pure

In the same way, the step 4 is carried out with 15 benzyl or allylbromides, 15 α-bromocarbonyl compounds and 15 acid chlorides in eitherDMF or NMP to give the expected compounds of TABLE 4. Examples 181 to228 of the present application are represented in TABLE 4. TABLE 4CHEMISTRY

181 2-[5-(benzyloxy)-2H- pyrazol-3-yl]-1H- benzoimidazole

182 2-[5-(3-Phenyl-allyloxy)- 2H-pyrazol-3-yl]-1H- benzoimidazole

183 2-[5-(2-Methyl-allyloxy)- 2H-pyrazol-3-yl]-1H- benzoimidazole

184 2-[5-(3,7-Dimethyl-octa- 2,6-dienyloxy)-2H- pyrazol-3-yl]-1H-benzoimidazole

185 2-[5-(3-Bromo- benzyloxy)-2H-pyrazol-3 yl]-1H-benzoimidazole

186 3-[5-(1H-Benzoimidazol 2-yl)-1H-pyrazol-3-yloxymethyl]-benzonitrile-

187 2-[5-(4-Trifluoromethyl- benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole

188 2-[5-(3,4-Dichloro- benzyloxy)-2H-pyrazol-3- yl]-1H-benzoimidazole

189 2-(5- Pentafluorophenylmetho- xy-2H-pyrazol-3-yl)-1H- benzoimidazole

190 2-[5-(4-tert-Butyl- benzyloxy)-2H-pyrazol-3 yl]-1H-benzoimidazole

191 2-[5-(2- Benzenesulfonylmethyl- benzyloxy)-2H-pyrazol-3yl]-1H-benzoimidazole

192 4-[5-(1H-Benzoimidazol 2-yl)-1H-pyrazol-3- yloxymethyl]-benzonitrile

193 2-[5-(Biphenyl-4- ylmethoxy)-2H-pyrazol-3 yl]-1H-benzoimidazole

194 2,3-Dichloro- benzenesulfonic acid 5- (1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

195 2-[5-(2-Morpholin-4-yl- ethoxy)-2H-pyrazol-3-yl]1H-benzoimidazole

196 2-[5-(2-Piperidin-1 -yl- ethoxy)-2H-pyrazol-3-yl]1H-benzoimidazole

197 2-[5-(3-Methoxy- benzyloxy)-2H-pyrazol-3 yl]-1H-benzoimidazole

198 2-[5-(1H-Benzoimidazol- 2-yl)-1H-pyrazol-3-yloxy]1 -p-tolyl-ethanone

199 1-[5-(1H-Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]3,3,4,4,4-pentafluoro- butan-2-one

200 2-[5-(1H-Benzoimidazol- 2-yl)-1H-pyrazol-3-yloxy]1-biphenyl-4-yl-ethanone

201 1-[5-(1H-Benzoimidazol 2-yl)-1H-pyrazol-3-yloxy]butan-2-one

202 2-[5-(1H-Benzoimidazol- 2-yl)-1H-pyrazol-3-yloxy]1-(4-dimethylamino-phenyl)-ethanone

203 2-[5-(1H-Benzoimidazol2-yl)-1H-pyrazol-3-yloxy]1-(3-phenyl-isoxazol-5- yl)-ethanone

204 2-[5-(1H-Benzoimidazol- 2-yl)-1H-pyrazol-3-yloxy]N-phenyl-acetamide

205 1-[5-(1H-Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]3,3-dimethyl-butan-2- one

206 1-Adamantan-1-yl-2-[5- (1H-benzoimidazol-2-yl)- 1H-pyrazol-3-yloxy]-ethanone

207 2-[5-(1H-Benzoimidazol 2-yl)-1H-pyrazol-3-yloxy]1-naphthalen-2-yl-ethanone

208 4-{2-[5-(1H- Benzoimidazol-2-yl)-1H- pyrazol-3-yloxy]-acetyl}-benzonitrile

209 6-{2-[5-(1H- Benzoimidazol-2-yl)-1H- pyrazol-3-yloxy]-acetyl}-3,4-dihydro-1H-quinolin- 2-one

210 2-[5-(1H-Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]1-(4-trifluoromethoxy- phenyl)-ethanone

211 5-{2-[5-(1H- Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-2-chloro benzenesulfonamide

212 2-[5-(1H-Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]1-(4-methoxy-phenyl)- ethanone

213 2-[5-(1H-Benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]1-cyclopropyl-ethanone

214 Isonicotinic acid 5-(1H- benzoimidazol-2-yl)-1H- pyrazol-3-yl ester

215 2,2-Dimethyl-propionic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

216 Benzyloxy-acetic acid 5- (1H-benzoimidazol-2-yl)- 1H-pyrazol-3-ylester

217 Benzoic acid 5-(1H- benzoimidazol-2-yl)-1H- pyrazol-3-yl ester

218 4-Methoxy-benzoic acid 5-(1H-benzoimidazol-2- yl)-1H-pyrazol-3-ylester

219 Phenyl-acetic acid 5-(1H benzoimidazol-2-yl)-1H- pyrazol-3-yl ester

220 2,3,4,5,6-Pentafluoro- benzoic acid 5-(1H benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

221 Cyclopropanecarboxylic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

222 2,2,3,3,4,4,4- Heptafluoro-butyric acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

223 Cyclopentanecarboxylic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

224 3-Phenyl-propionic acid 5-(1H-benzoimidazol-2- yl)-1H-pyrazol-3-ylester

225 Biphenyl-4-carboxylic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

226 3,5-Bis-trifluoromethyl- benzoic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

227 4-Trifluoromethyl- benzoic acid 5-(1H- benzoimidazol-2-yl)-1H-pyrazol-3-yl ester

228 Thiophene-2-carboxylic benzoimidazol-2-yl)-1H- pyrazol-3-yl ester

EXAMPLE 229 Pharmaceutical Composition

Tablets corresponding to the formula below were prepared:

-   Product of Example 1 . . . 0.2 g-   Excipient for a finished tablet containing . . . 1 g-   (details of the excipient: lactose, talc, starch, magnesium    stearate).

Example 1 is taken as pharmaceutical preparation example, it beingpossible for this preparation to be produced, if desired, with otherproducts in examples in the present application.

EXAMPLE 230 (a)5,6-Dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole

A mixture of5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[90 mg, Reference Example 1(a)], hydrochloric acid (2 mL, 4N) andethanol (4 mL) was heated at reflux temperature for 16 hours then cooledto room temperature. The pH of the reaction mixture was adjusted to 7 byaddition of saturated sodium bicarbonate solution. The resulting solidwas filtered, then washed with water and then dried in a vacuum oven togive 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole(38 mg). LC-MS (METHOD A): R_(T)=2.22 minutes; 259 (M+H)⁺.

(b)6-Chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(b)] there was prepared6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole.

(c)6-Chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(c)] there was prepared6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole.

(d)2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(d)] there was prepared2-(5-methylsulfanyl-1H-pyrazol-3-yl-5-trifluoromethyl-1H-benzoimidazole.

(e)2-(5-Cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(e)] there was prepared2-(5-cyclopropylmethylsulfanyl-1-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole.LC-MS (METHOD A): R_(T)=2.47 minutes; 299 (M+H)⁺.

(f) 2-(5-Ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using5,6-dimethyl-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(f)] there was prepared2:5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole. LC-MS(METHOD A): R_(T)=2.32 minutes; 273 (M+H)⁺.

(g)5,6-Dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using5,6-dimethyl-2-[5-(pyridin-3-yl)methylsulfanyl-1H-pyrazol-3-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(g)] there was prepared5,6-dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazoleas a colourless solid.

(h) 5-Fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using5-fluoro-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(h)] there was prepared5-fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole. MS:249 (M+H)⁺.

(i)5,6-Dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(i)] there was prepared5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole.

(j) 4-Methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(1)] there was prepared4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole. MS: 245(M+H)⁺.

(k) 5,6-Dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(k)] there was prepared5,6-dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole.

(l)6-Chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using6-chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(l)] there was prepared6-chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1H-benzoimidazole.

(m)5,6-Dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole

By proceeding in a similar manner to Example 230(a) above but using5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 1(m)] there was prepared5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole.

EXAMPLE 231(2-(5-Ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazolehydrochloride

A mixture of3,3-bis-ethylsulfanyl-1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[˜0.78 mmole, Reference Example 2(j)] and hydrazine hydrate (500 μL) inethanol (6 mL) was heated at reflux temperature for 18 hours, thenevaporated. The residue was purified on the Flashmaster to give2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazolewhich was treated with ethanol (6 mL) and hydrochloric acid (3 mL). Thismixture was heated at reflux temperature for 18 hours and thenevaporated to give2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazolehydrochloride. LC-MS (METHOD A): R_(T)=2.17 minutes; 275 (M+H)⁺.

EXAMPLE 232 (a)5-Methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole

A mixture of2-(bis-methylsulfanyl-methylene)-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one[˜0.49 mmole, Reference Example 2(l)] and hydrazine hydrate (200 μL) inethanol (6 mL) was heated at reflux temperature for 2 days, thenevaporated. The mixture was then treated with hydrochloric acid (4 mL,4N) and heating was continued at reflux temperature for a further 24hours. The reaction mixture was cooled, then neutralised by addition ofsodium hydroxide solution (4N) and then extracted with dichloromethane.The extract was evaporated to give5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole.MS: 287 (M+H)⁺.

(b)2-(5-(4-methoxy-benzylsulfanyl)-4-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole

By proceeding in a similar manner to Example 233(a) above but using2-[bis-(4-methoxy-benzylsulfanyl)-methylene]-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one[Reference Example 2(m)] there was prepared2-(5-(4-methoxy-benzylsulfanyl)-4-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole.MS: 393 (M+H)⁺.

(c)2-(5-Benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole

By proceeding in a similar manner to Example 232(a) above but using2-(bis-benzylsulfanyl-methylene)-3-methyl-1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-one[Reference Example (2n)] there was prepared2-(5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole.MS: 363 (M+H)⁺.

(d)2-(5-Methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole

By proceeding in a similar manner to Example 232(a) above but using1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-2-methyl-3-(bis-methanesulfanyl)-1-propenone[Reference Example 2(r)] there was prepared2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole.

(e)2-(5-Methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole

By proceeding in a similar manner to Example 232(a) above but using1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-2-methyl-3-bis-methanesulfanyl)-1-propenone[Reference Example 2(t)] there was prepared2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole.

EXAMPLE 233 (a) 3-(5-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

A solution of 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [91mg, Example 239(a)] in ethanol (40 mL), under nitrogen, was treated withpalladium on carbon (spatula tip, 5%). The mixture was stirred underhydrogen for 3 hours and then filtered through Celite. The filter padwas washed well with dichloromethane. The combined filtrate and washingswere evaporated to give3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (116 mg). LC-MS(METHOD A): R_(T)=2 minutes; 234 (M+H)⁺.

(b) 3-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 233(a) above but using5,6-dichloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [Example239(b)] there was prepared3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine. LC-MS(METHOD A): R_(T)=2.37 minutes; 268 (M+H)⁺.

(c) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 233(a) above but using5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [Example249(a)] there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine as a brownsolid. LC-MS (METHOD B): R_(T)=2.29 minutes; 228.25 (M+H)⁺.

(d) 3-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 233(a) above but using5-ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [Example249(b)] there was prepared345-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine as abrown solid. LC-MS (METHOD B): R_(T)=2.14 minutes, 242.20 (M+H)⁺.

(e) 3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 233(a) above but using6-chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [0.7 g,Example 249(c)] there was prepared3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.54g) as a brown foam. MS 264 (M+H)⁺.

(f) 3-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 233(a) above but using5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [373 mg, Example257(f)] there was prepared3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (257 mg) as adark brown solid. LC-MS (Method H): R_(T)=1.23 minutes, 230.25 (M+H)⁺,228.25 (M−H)⁻.

(g) 3-(5-Ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a manner similar to Example 233(a) above but using5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [407 mg, Example252(c)] there was prepared3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (375 mg) as adark brown oil. LC-MS (Method H): R_(T)=1.43 minutes, 244.26 (M+H)⁺,242.28 (M−H)⁻.

(h) 3-(5-Fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a manner similar to Example 233(a) above but using5-fluoro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [Example249(d)] there was prepared3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.590g) as a brown solid. LC-MS (METHOD J): R_(T)=2.25 minutes, MS: 232.29(M+H)⁺.

(i) 3-(5-Trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a manner similar to Example 233(a) above but using5-trifluoromethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole[Example 249(e)] there was prepared3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl]-1H-pyrazol-4-ylamine (0.920g) as a brown solid. LC-MS (METHOD J): R_(T)=2.76 minutes, 284.23(M+H)⁺.

(j) 3-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a manner similar to Example 233(a) above but using5-trifluoromethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [Example249(f)] there was prepared3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (0.150g) as a brown solid. LC-MS (METHOD B): R_(T)=3.00 minutes, 268.16(M+H)⁺.

(k) 2-(4-Amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acidmethyl ester

By proceeding in a manner similar to Example 233(a) above but using2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylester [Example 249(h)] there was prepared2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylester (1.10 g) as an off-white solid. LC-MS (METHOD B): R_(T)=2.40minutes, 258.17 (M+H)⁺.

EXAMPLE 234 (a) 3-(1H-Benzoimidazol-2-yl)-1H-indazole

A mixture of 1,2-diaminobenzene (108 mg), indazole-3-carboxylic acid(118 mg) and polyphosphoric acid (1 mL) was heated at 150-160° C. for 24hours. The mixture was cooled, then diluted with ice water (10 mL) andthen treated with ethyl acetate (10 mL). The aqueous layer was basifiedby addition of solid potassium carbonate. The layers were separated andthe aqueous layer was extracted with ethyl acetate (10 mL). The combinedorganic phases were dried and then evaporated. The residue was subjectedto chromatography on silica eluting with a mixture of heptane and ethylacetate to give 3-(1H-benzoimidazol-2-yl)-1H-indazole (78 mg). LC-MS(METHOD A): R_(T)=1.28 minutes; 235 (M+H)⁺.

(b) 3-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a similar manner to Example 234(a) above but using4-methoxy-1,2-diaminobenzene hydrochloride there was prepared3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole as a solid.

LC-MS (METHOD A): R_(T)=1.28 minutes; 265 (M+H)⁺.

(c) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone

By proceeding in a similar manner to Example 234(a) above but using3,4-diaminobenzophenone there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone as a solid.

LC-MS (METHOD A): R_(T)=1.73 minutes; 339 (M+H)⁺.

(d) 2-(1H-Indazol-3-yl)-3H-benzoimidazol-4-ol

By proceeding in a similar manner to Example 234(a) above but using2,3-diaminophenol there was prepared2-(1H-indazol-3-yl)-3H-benzoimidazol-4-ol as a solid. LC-MS (METHOD A):R_(T)=1.63 minutes; 251 (M+H)⁺.

(e) 2-Phenyl-1H-imidazol[4,5-b]pyrazine

By proceeding in a similar manner to Example 234(a) above but using2,3-diaminopyrazine [Reference Example 9] and benzoic acid there wasprepared 2-phenyl-1H-imidazol[4,5-b]pyrazine as a pale brown solid, mp239-240° C. HPLC (METHOD A1): R_(T)=10.18 minutes.

(f) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a similar manner to Example 234(a) above but using1,2-diamino-4,5-dimethylbenzene there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole (28 mg). LC-MS(METHOD A):R_(T)=1.34 minutes; 263 (M+H)⁺.

(g) 2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine

By proceeding in a similar manner to Example 234(a) above but using3,4-diaminopyridine there was prepared2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine as a solid. MS: 236(M+H)⁺. HPLC (METHOD A): R_(T)=2.48 minutes.

(h) 2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine

By proceeding in a similar manner to Example 234(a) above but using2,3-diaminopyridine there was prepared2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine as a solid. MS: 236(M+H)⁺. HPLC (METHOD A): R_(T)=2.49 minutes.

EXAMPLE 235 (a) 2-(1H-Pyrazol-3yl)-1H-benzoimidazole

A mixture of 1H-pyrazole-3-carbaldehyde (0.961 g, Reference Example 10),o-phenylenediamine (0.973 g), sodium bisulfite (1.898 g) and drydimethylformamide (10 mL) was stirred at reflux for 2 hours, then cooledto room temperature and then poured onto cracked ice (35 g). The mixturewas filtered and the solid was washed with aqueous sodium bicarbonateand then with water. The solid was vacuum dried at 70° C. and thenrecrystallised from ethanol to give 2-(1H-pyrazol-3yl)-1H-benzoimidazole(0.645 g) as a pale yellowish solid, mp 335-338° C. [Elementalanalysis:—C, 62.56%; H, 4.04%; N, 29.14%. Calculated for C₁₀H₈N₄:—C,65.19%; H, 4.39%; N, 30.42%].

(b) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole

By proceeding in a similar manner to Example 235(a) above but using3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester[Reference Example 20(a)] and 4,5-dimethylbenzene-1,2-diamine there wasprepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole asa white solid.

LC-MS (METHOD B): R_(T)=2.35 minutes; 289 (M+H)⁺.

(c) 3-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester[Reference Example 20(a)] and 4-ethyl-5-methyl phenylene diamine[Reference Example 30], and subjecting the reaction product to flashcolumn chromatography on silica eluting with a mixture of ethyl acetateand 40-60 petrol (1:1, v/v), there was prepared,3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole as apale yellow solid.

LC-MS (METHOD B): R_(T)=2.48 minutes; 307 (M+H)⁺.

(d) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using5-fluoro-1H-indazole-3-carbaldehyde [Reference Example 6(c)] and4,5-dimethylbenzene-1,2-diamine there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole as a brownsolid.

LC-MS (METHOD B): R_(T)=2.41 minutes; 281 (M+H).

(e) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using6-fluoro-1H-indazole-3-carbaldehyde [Reference Example 6(d)] and4,5-dimethylbenzene-1,2-diamine there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole (0.104 g) asa brown solid. MS: 281 (M+H)⁺. HPLC (METHOD B1): R_(T)=23.6 minutes.

(f) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using5-methyl-1H-indazole-3-carbaldehyde [Reference Example 6(e)] there wasprepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole asa brown solid. LC-MS (METHOD B): R_(T)=2.35 minutes; 277 (M+H)⁺.

(g) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using6-methoxy-1H-indazole-3-carbaldehyde [Reference Example 6(f)] there wasprepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole asa pale orange solid. LC-MS (METHOD B): R_(T)=2.52 minutes; 293 (M+H)⁺.

(h) 5,6-Dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 235(a) above but using4-phenyl-1H-pyrazole-3-carbaldehyde [Reference Example 6(g)] there wasprepared 5,6-dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole asa white solid. LC-MS (METHOD B): R_(T)=2.35 minutes; 289 (M+H)⁺.

(i) 3-(5-Ethyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using4-ethyl-phenylene diamine [Reference Example 29(a)], a reactiontemperature of 160° C. and subjecting the reaction product to flashcolumn chromatography on silica eluting with a mixture of ethyl acetateand hexane (2:1) there was prepared3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole as an off-white solid.LC-MS (Method D): R_(T)=23.13 minutes, 263.3 (M+H)⁺.

(j) 3-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-ethyl-5-methyl-phenylene diamine [Reference Example 30(a)] there wasprepared 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl-1H-indazole as anoff-white solid. LC-MS (Method D): R_(T)=23.79 minutes, 277.3 (M+H)⁺.

(k) 3-(5-Isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-isopropyl-5-methyl-phenylene diamine [Reference Example 30(b)] therewas prepared 3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazoleas an off-white solid. MS: 291.03 (N+H)⁺. HPLC (METHOD B1): R_(T)=23.39minutes.

(l) 3-(5-Bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-bromo-5-methyl-phenylene diamine [Reference Example 30(c)] there wasprepared 3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole as anoff-white solid. MS: 329.09 (M+H)⁺. HPLC (METHOD B1): R_(T)=22.74minutes.

(m) 3-(5-Bromo-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-bromo-phenylene diamine [Reference Example 30(e)] there was prepared3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole as a brown solid. LC-MS(Method D): R_(T)=23.46 minutes, 315.15 (M+1)⁺.

(n) 3-(5-(3-Cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using3′,4′-diaminobiphenyl-3-carbonitrile [Reference Example 30(f)] there wasprepared 3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 335.3 (M+H)⁺. HPLC (METHOD B1): R_(T)=21.47 minutes.

(o) 3-(5-(Pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-(pyridine-3-yl) benzene-1,2-diamine [Reference Example 30(g)] therewas prepared 3-(5-(pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 312.2 (M+H)⁺. HPLC (METHOD B1): R_(T)=8.58 minutes.

(p) 3-(6-Methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using6-methylbiphenyl-3,4-diamine [Reference Example 30(h)] there wasprepared 3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 325.3 (M+H)⁺. HPLC (METHOD B1): R_(T) 14.48 minutes.

(q) 3-(5-Phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-biphenyl-3,4-diamine [Reference Example 30(i)] there was prepared3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole as a white solid. MS:311.2 (M+H)⁺. HPLC (Method D): R_(T)=24.54 minutes.

(r) 3-(5-(2-Fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using2′-fluorobiphenyl-3,4-diamine diamine [Reference Example 30(j)] therewas prepared 3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole asa white solid. MS: 329.2 (M+H)⁺. HPLC (METHOD B1): R_(T)=22.54 minutes.

(s) 3-(5-(3,4-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-benzo[1,3]dioxol-5-ylbenzene-1,2-diamine [Reference Example 30(k)]there was prepared3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 355.2 (M+H)⁺. HPLC (METHOD B1): R_(T)=22.04 minutes.

(t) 3-(5-(2-Methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using2′-methoxybiphenyl-3,4-diamine [Reference Example 30(1)] there wasprepared 3-(5-(2-methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 341.2 (M+H)⁺. HPLC (METHOD B1): R_(T)=22.09 minutes.

(u) 3-(5-(4-Chlorophenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4′-chlorobiphenyl-3,4-diamine [Reference Example 30(m)] there wasprepared 3-(5-(4-chloro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. MS: 345.2 (M+H)⁺. HPLC (METHOD B1): R_(T)=23.71 minutes.

(v) 3-(5-(4-Methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4′-methylbiphenyl-3,4-diamine diamine [Reference Example 30(n)] therewas prepared 3-(5-(4-methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole asa white solid. MS: 325.1 (M+H)⁺. HPLC (METHOD C1): R_(T)=15.22 minutes.

(w) 3-(5-Benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-benzyloxybenzene-1,2-diamine [Reference Example 30(o)] there wasprepared 3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole as a whitesolid. MS: 339.3 (M+H)⁺. HPLC (METHOD B1): R_(T)=22.32 minutes.

(x) 3-(5,6-Methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but usingbenzo[1,3]dioxole-5,6-diamine [Reference Example 30(p)] there wasprepared 3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole as awhite solid. LC-MS (METHOD B): R_(T)=2.25 minutes; 279.22 (M+H)⁺.

(y) 3-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4,5-dimethoxybenzene-1,2-diamine [Reference Example 30(q)] there wasprepared 3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole as a whitesolid. LC-MS (METHOD B): R_(T)=2.16 minutes; 295.26 (M+H)⁺.

(z) 3-(5,6-Diethyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4,5-diethylbenzene-1,2-diamine [Reference Example 30(r)] there wasprepared 3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole as a whitesolid. LC-MS (METHOD B): R_(T)=2.49 minutes; 291.32 (M+H)⁺.

(aa) 3-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using3,4-dimethylbenzene-1,2-diamine there was prepared3-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole as a white solid.LC-MS (METHOD B): R_(T)=2.31 minutes; 263.24 (M+H)⁺.

(ab) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carbonitrile

By proceeding in a manner similar to Example 235(i) above but using3,4-diaminobenzonitrile amine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile as a white solid.

LC-MS (Method D): R_(T)=21.81 minutes, MS: 260.10 (M+H)⁺.

(ac) 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using3,4-diaminobenzoic acid, methyl ester there was prepared3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole as a whitesolid. LC-MS (Method D): R_(T)=22.13 minutes, 293.16 (M+H)⁺.

(ad) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using5-ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester [ReferenceExample 20(d)] there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole as a paleorange solid. MS: 307 (M+H)⁺. HPLC (METHOD B1): R_(T)=13.58 minutes.

(ae) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acidethyl ester

By proceeding in a manner similar to Example 235(a) above but using3-formyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example 6(i)]there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl-pyrazole-4-carboxylic acid ethylester as a pale brown solid. LC-MS (METHOD B): 2.56 minutes; 285 (M+H)⁺.

(af)2-(4-Isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid methyl ester

By proceeding in a manner similar to Example 235(a) above but using3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example6(j)] and methyl-3,4-diamino benzoate there was prepared2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid methyl ester as a yellow solid. LC-MS (METHOD B): 2.99 minutes; 328(M+H)⁺.

(ag)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid ethyl ester

By proceeding in a manner similar to Example 235(a) above but using3-formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester [ReferenceExample 6(k)) there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid ethyl ester as a white solid. LC-MS (METHOD B): R_(T)=2.59 minutes;299 (M+H)⁺.

(ah)3-(1,5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylicacid cyclopropylamide

By proceeding in a manner similar to Example 235(a) above but usingindane-5,6-diamine (130 mg) and 3-formyl-1H-pyrazole-4-carboxylic acidcyclopropylamide [150 mg, Reference Example 6(q)] and subjecting thereaction product to chromatography on silica [eluting with ethylacetate/gradient 75 to 0% heptane] followed by trituration with acetone,there was prepared3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylicacid cyclopropylamide (31 mg) as a white solid. LC-MS (Method A):R_(T)=2.85 minutes, 308 (M+H)⁺.

(ai)3-(5-Methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide

By proceeding in a manner similar to Example 235(a) above but using3-formyl-pyrazole-4-carboxylic acid-isopropylamide [198 mg, ReferenceExample 60)] and 4-methoxy-5-methyl-benzene-1,2-diamine [166 mg,Reference Example 29(b)] and subjecting the reaction product to flashchromatography on silica eluting with dichloromethane/methanol (95:5)followed by recrystallisation from a mixture of ethyl acetate andn-pentane there was prepared3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide (145 mg) as a white solid. LC-MS (Method H):R_(T)=2.09 minutes, 314.27 (M+H)⁺, 312.29 (M−H)⁻.

(aj) 3-[5-(2-Morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole

By proceeding in a manner similar to Example 235(i) above but using4-(2-morpholin-4-yl-ethoxy)-benzene-1,2-diamine [Reference Example29(c)] and subjecting the reaction product to preparative LC-MS therewas prepared3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole (25mg) as a white solid. MS: 364 (M+H)⁺. HPLC (METHOD B1): R_(T)=19.38minutes.

(ak) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid (2-methoxy-ethyl)-amide

By proceeding in a manner similar to Example 235(i) above but using4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylicacid (2-methoxy-ethyl)-amide [Reference Example 6(n)] there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide (87 mg) as a cream solid. LC-MS (METHOD L):R_(T)=4.23 minutes, 314.2 (M+H)⁺.

(al) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid propylamide

By proceeding in a manner similar to Example 6(i) above but using4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylicacid propylamide [Reference Example 6(o)] there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidpropylamide (73 mg) as a pale yellow solid. LC-MS (METHOD L): R_(T)=4.94minutes, 298.29 (M+H)⁺.

(am) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylicacid (tetrahydro-pyran-4-yl)-amide

By proceeding in a manner similar to Example 235(i) above but using4,5-dimethyl-1,2-phenylenediamine and 3-formyl-1H-pyrazole-4-carboxylicacid (tetrahydro-pyran-4-yl)-amide [Reference Example 6(p)] andrecrystallising the reaction product from methanol there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-amide (228 mg) as a white solid. LC-MS (METHODR): R_(T)=9.40 minutes, 360 (M+H)⁺.

(an)3-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile

By proceeding in a manner similar to Example 235(i) above but using4-ethyl-5-methyl-phenylene diamine [Reference Example 30(a)] and3-formyl-1H-indazole-5-carbonitrile [Reference Example 68] there wasprepared3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile(133 mg) as a pale yellow solid. MS: 302 (M+H)⁺. HPLC (METHOD B1):R_(T)=16.45 minutes.

(ao)3-(5-Difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide

By proceeding in a manner similar to Example 235(i) above but using4-difluormethoxy-benzene-1,2-diamine [Reference Example 30(y)] and3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example6(j)] there was prepared3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide (118 mg) as a white solid. LC-MS (METHOD L):R_(T)=10.46 minutes, 336.19 (M+H)⁺.

(ap)3-(5-Difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid cyclopropylamide

By proceeding in a manner similar to Example 235(ao) above but using3-formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide [ReferenceExample 6(q)] there was prepared3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid cyclopropylamide (63 mg) as a white solid. LC-MS (METHOD L):R_(T)=10.18 minutes, 334.17 (M+H)⁺.

(aq)3-(6-Ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide

By proceeding in a manner similar to Example 235(i) but using4-ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example 30(z)]and 3-formyl-pyrazole-4-carboxylic acid isopropylamide [ReferenceExample 6(j)] there was prepared3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylicacid isopropylamide (115 mg) as an off-white solid. LC-MS (METHOD L):R_(T)=11.34 minutes, 328.24 (M+H)⁺.

(ar) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitriledihydrochloride

By proceeding in a manner similar to Example 235(i) above but (i) using4,5-dimethyl-phenylene diamine and 3-formyl-1H-indazole-5-carbonitrile[Reference Example 68] (ii) treating a suspension of the reactionproduct in methanol with a solution of hydrochloric acid (4M) in1,4-dioxane followed by evaporation of the mixture (iii) trituration ofthe residue with methanol and (iv) recrystallisation from diethyl ether,there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitriledihydrochloride (133 mg) as an off-white solid. LC-MS (METHOD B):R_(T)=2.32 minutes. MS: 288 (M+H)⁺.

(as) 3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 235(a) above but using4-nitrophenylenediamine there was prepared3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole as red solid. MS: 280.17(M+H)⁺. HPLC (Method B1): R_(T)=3.00 minutes.

EXAMPLE 236 2-(5-Methyl-1H-pyrazol-3-yl)-1H-benzoimidazole

A mixture of o-phenylenediamine (1.08 g) and5-methylpyrazole-3-carboxylic acid (1.266 g) was finely ground and thefinely ground material was heated at 160° C. for 3 hours and then cooledto ambient temperature. The reaction mixture was recrystallised fromethyl alcohol (50 mL) to give a light blue solid (0.27 g). The filtrategave another crop (0.1 g) on standing. The combined solids wererecrystallised from ethyl alcohol to give2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole (223 mg) as a lilaccoloured solid, mp 322-324° C. [Elemental analysis:—C, 66.54%; H, 4.80%;N, 28.14%. Calculated for C₁₁H₁₀N₄:—C, 66.64%; H, 5.09%; N, 28.27%].

EXAMPLE 237 2-(5-Ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole

A mixture of trifluoroacetic acid (6 mL) and2-(5-ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(300 mg, Reference Example 11) was stirred at 50° C. for 1.5 hours. Thereaction mixture was evaporated and the residue was partitioned betweenethyl acetate and water (pH 10). The organic layer was dried and thenevaporated. The residue was subjected to chromatography on silicaeluting with a mixture of dichloromethane and methanol (9:1, v/v) andthen recrystallised from toluene to give2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole (0.1 g) as a colourlesssolid, mp 217-219.5° C. [Elemental analysis:—C, 62.26%; H, 5.23%; N,23.44%. Calculated for C₁₂H₁₂N₄O:—C, 63.15%; H, 5.30%; N, 24.55%].

EXAMPLE 238 2-(5-Methylsulfanyl-isoxazol-3-yl)-1H-benzoimidazole

A mixture of2-(5-methylsulfanyl-isoxazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(160 mg, Reference Example 12), methanol (12 mL) and concentratedaqueous hydrochloric acid (2.45 mL) were heated at reflux for fourhours, then cooled and then evaporated. The residue was treated withaqueous sodium bicarbonate and the mixture was extracted with ethylacetate. The extracts were dried and then evaporated to give2-(5-methylsulfanyl-isoxazol-3-yl)-1H-benzoimidazole (96 mg) as an offwhite solid, mp 179-181° C. ¹H-NMR [(CD₃)₂SO]: δ 4.65 (s, 3H), 9.00 (s,1H), 9.15-9.6 (m, 4H).

EXAMPLE 239 (a) 5-Chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid(4N) was treated with 4-nitro-pyrazole-3-carboxylic acid (826 mg) thenheated at reflux temperature, under nitrogen. The reaction mixture wascooled to room temperature when the pH was adjusted to 8 by addition ofammonium hydroxide and the mixture was extracted with ethyl acetate. Theextracts were evaporated to give5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole.

(b) 5,6-dichloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 239(a) above but using4,5-dichloro-1,2-diaminobenzene there was prepared5,6-dichloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole.

EXAMPLE 240 (Benzoimidazol-2-yl)-5-methylthio-3-pyrazole

A mixture of 1-[(3,3-bis(methylthio))benzoimidazol-2-yl]propen-2-one[5.5 g, Reference Example 15], hydrazine hydrate (1.02 g) andacetonitrile (50 mL) was stirred at reflux for 18 hours. The reactionmixture was cooled, and the precipitate was isolated by filtration.Recrystallisation from aqueous ethanol provided(benzoimidazol-2-yl)-5-methylthio-3-pyrazole (3.36 g) as a beigecrystalline solid, m.p. 242° C. [Elemental analysis: Found: C, 57.8; H,4.5; N, 24.0. Calculated for C₁₁H₁₀N₄S: C, 57.37; H, 4.38; N, 24.33].

EXAMPLE 241 (a)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole

4,5-Dimethylbenzene-1,2-diamine (90 mg) and4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, ReferenceExample 17(a)] were mixed in a glass vial then subjected to microwaveradiation (900 W, domestic oven) twice for two minutes. The resultingsolid was subjected to flash column chromatography on silica elutingwith a mixture of ethyl acetate and hexane (85:15, v/v) to give3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole(30 mg) as a pale brown solid. LC-MS (METHOD B): R_(T)=2.28 minutes; 267(M+H)⁺.

(b) 2-(5-Isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole

By proceeding in a manner similar to Example 241 (a) above, but using5-isopropyl-1H-pyrazole-3-carboxylic acid [Reference Example 17(b)]there was prepared2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole (80 mg)as a brown solid. LC-MS (METHOD B): R_(T)=2.27 minutes; 255 (M+H)⁺.

(c) 2-(5-Ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole

By proceeding in a manner similar to Example 241(a) above but using5-ethyl-1H-pyrazole-3-carboxylic acid [Reference Example 17(c)], andtriturating the brown solid reaction product with a mixture of ethylacetate and hexane (1:1, v/v), there was prepared2-(5-ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole as a lightbrown solid. LC-MS (METHOD B): R_(T)=2.22 minutes; 241 (M+H)⁺.

(d)5,6-Dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 214(a) above but using1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid [ReferenceExample 17(f)] and triturating the reaction product with ethyl acetate,ether and methanol, there was prepared5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole(50 mg) as an off-white solid. MS: 253 (M+H)⁺. HPLC (METHOD B1):R_(T)=11.17 minutes.

EXAMPLE 242 (a)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole

A mixture of 4,5-dimethylbenzene-1,2-diamine (70 mg) and4-fluoro-1H-indazole-3-carbaldehyde [80 mg, Reference Example 20(b)] indimethylformamide (8 ml) was heated to 120° C. for 30 minutes and thenat 100° C. for 16 hours. The reaction mixture was cooled, then dilutedwith ethyl acetate and then washed five times with brine. The organicphase was dried over magnesium sulfate and then evaporated. The residuewas subjected to flash column chromatography on silica eluting with amixture of 40/60 petrol and ethyl acetate (1:5, v/v) to give345,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole (104 mg) as alight brown solid. MS: 281 (M+H)⁺. HPLC (METHOD B1): R_(T)=10.08minutes.

(b) 4-Chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 242(a) above but using4-chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester [ReferenceExample 20(c)] there was prepared4-chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole (25 mg) asan off-white solid. MS: 299 (M+H)⁺. HPLC (METHOD B1): R_(T)=10.59minutes.

(c) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole

By proceeding in a manner similar to Example 242(a) above but using5-chloro-1H-indazole-3-carbaldehyde [Reference Example 6(h)] there wasprepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole (25mg) as a pale brown solid. LC-MS (METHOD D): R_(T)=24.24 minutes, 299(M+H)⁺.

EXAMPLE 243 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol

A solution of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole [34 mg,Example 235(b)] at 0° C. was treated with a solution of boron tribromidein dichloromethane (0.30 mL, 1M). The mixture was then heated at refluxtemperature for 4 hours, then cooled and then treated dropwise withwater. The pH was adjusted to between 7 and 8 by the addition ofsaturated aqueous sodium bicarbonate solution and this mixture was thenextracted twice with ethyl acetate. The combined extracts were washedwith brine, then dried over magnesium sulfate and then evaporated. Thepale yellow solid residue was subjected to flash column chromatographyon silica eluting with a mixture of ethyl acetate and triethylamine(99:1, v/v) to yield3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol (23 mg) as awhite solid. LC-MS (METHOD B): R_(T)=2.19 minutes; 279 (M+H)⁺.

EXAMPLE 244 (a) 3-(5-n-Propyl-1H-benzoimidazol-2-yl)-1H-indazole

A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, ReferenceExample 30(d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml)was treated with indazole-3-carboxaldehyde [Reference Example 6(1)]. Thereaction mixture was heated in a Smith Creator microwave at 200° C. for13 minutes then partitioned between ethyl acetate and water. The organiclayer was washed with brine, then dried over magnesium sulfate and thenevaporated. The residue was subjected to flash column chromatography onsilica eluting with a mixture of ethyl acetate and hexane (3:1) to give3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole (74 mg) as a pale brownsolid. MS: 277.3 (M+H)⁺. HPLC (METHOD B1): R_(T)=12.81 minutes.

(b) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide

By proceeding in a manner similar to Example 244(a) above but using3,4-diamino-N-benzyl-benzenesulfonamide[Reference Example 30(x)] andheating at 230° C. there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide (235mg) as a white solid. LC-MS (METHOD L): R_(T)=6.35 minutes, 404.20(M+H)⁺.

(c) 3-(5-Methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole

By proceeding in a manner similar to Example 244(a) above but using4-methanesulfonyl-benzene-1,2-diamine [Reference Example 49(f)] andheating at 210° C. there was prepared3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole (105 mg) as awhite solid. LC-MS (METHOD L): R_(T)=5.71 minutes, 313.23 (M+H)⁺.

EXAMPLE 245 [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol

A stirred solution of[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone [200 mg,Example 234(c)] in tetrahydrofuran (10 mL), at −78° C. and under anatmosphere of nitrogen, was treated dropwise with a solution ofdiisobutylaluminium hydride in tetrahydrofuran (1.18 mL, 1N). Thereaction mixture was warmed to ambient temperature, then stirred for 16hours and then partitioned between ether and sodium hydroxide solution(2N). The organic phase was washed with water, then with brine, thendried over magnesium sulfate and then evaporated. The residue wassubjected to flash column chromatography on silica eluting with amixture of ethyl acetate and hexane (3:1, v/v) to give[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol (161 mg) as awhite solid. LC-MS (Method D): R_(T)=21.89 minutes, 341.3 (M+H)⁺.

EXAMPLE 246 (a) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylicacid, ethylamide

A stirred solution of[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid [130 mg,Example 247(a)], hydroxybenzatriazole (189 mg) and diisopropylethylamine (732 μL) in dimethylformamide (3 mL) was treated withethylamine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (267 mg). The reaction mixture was heated at 80° C.overnight and then partitioned between ethyl acetate and 5% citric acid.The aqueous layer was re-extracted with ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodium hydrogencarbonate solution, then with brine, then dried over magnesium sulfateand then evaporated. The residual oil was subjected to preparative HPLCto give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,ethylamide as a white solid. LC-MS (METHOD B): R_(T)=2.37 minutes;306.27 (M+H)⁺.

(b) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,methylamide

By proceeding in a manner similar to Example 246(a) above but usingmethylamine, there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, methylamide asa white solid.

LC-MS (METHOD B): R_(T)=2.28 minutes; 292.30 (M+H)⁺.

(c) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,dimethylamide

By proceeding in a manner similar to Example 246(a) above but usingdimethylamine, there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, dimethylamideas a white solid. LC-MS (METHOD B): R_(T)=2.38 minutes; 306.27 (M+H)⁺.

(d) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,isopropylamide

By proceeding in a manner similar to Example 246(a) above but usingisopropylamine, there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, isopropylamideas a white solid.

LC-MS (METHOD B): R_(T)=2.48 minutes; 320.30 (M+H)⁺.

(e) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid,benzylamide

By proceeding in a manner similar to Example 246(a) above but usingbenzylamine, there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzylamide asa white solid.

LC-MS (METHOD B): R_(T)=2.68 minutes; 368.27 (M+H)⁺.

(f) [2-(Indazol-3-yl-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide

By proceeding in a manner similar to Example 246 (a) above but usinganiline, there was prepared[2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide as awhite solid.

LC-MS (METHOD B): R_(T)=2.73 minutes; 354.26 (M+H)⁺.

(g) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisopropylamide

By proceeding in a manner similar to Example 246(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid[Example 247(b)] and isopropylamine, and subjecting the reaction productto flash chromatography on silica eluting with a mixture ofdichloromethane and methanol (19:1, v/v), there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisopropylamide as an off-white solid. LC-MS (METHOD B): R_(T)=2.67minutes; 298 (M+H)⁺.

(h) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid[Example 247(b)] and 2-amino-2-methyl-1-propanol, and subjecting thereaction product to flash chromatography on silica eluting with amixture of dichloromethane and methanol (19:1, v/v), there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide as a pale yellow solid.

LC-MS (METHOD B): R_(T)=2.63 minutes; 328 (M+H)⁺.

(i)2-(4-Isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (pyridin-3-ylmethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid [Example 247(c)] and 3-aminomethyl)pyridine there was prepared2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (pyridin-3-ylmethyl)-amide as a white solid. LC-MS (METHOD B):R_(T)=2.49 minutes; 404 (M+H)⁺.

(j)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid cyclopropylamide

By proceeding in a manner similar to Example 246(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid [Example 247(d)] and cyclopropylamine, and subjecting the reactionproduct to flash chromatography on silica eluting with a mixture ofdichloromethane and methanol (119:1, v/v), there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid cyclopropylamide as a white solid. LC-MS (METHOD B): R_(T)=2.67minutes; 310 (M+H)⁺.

(k)2-(4-Isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid phenylmethyl-amide

By proceeding in a manner similar to Example 246(a) above but using2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid [Example 247(c)] and benzylamine there was prepared2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid phenylmethyl-amide as a pale yellow solid. LC-MS (METHOD B):R_(T)=3.17 minutes; 403 (M+H)⁺.

(l)2-(4-Isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (pyridin-2-ylmethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid [Example 247(c)] and 2-(aminomethyl)pyridine there was prepared2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (pyridin-2-ylmethyl)-amide as an off-white solid. LC-MS (Method D):R_(T)=9.33 minutes, 367.28 (M+H)⁺.

(m) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using3-(aminomethyl)pyridine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(pyridin-3-ylmethyl)-amide (42.2 mg) as an off white solid. LC-MS(Method L): R_(T)=4.96 minutes, 367.19 (M−H)⁻.

(n) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid3-methyl-benzylamide

By proceeding in a manner similar to Example 246(a) above but using3-methylbenzylamine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid3-methyl-benzylamide (33.4 mg) as a white solid. MS: 382.52 (M+H)⁺. HPLC(Method B1): R_(T)=16.22 minutes.

(o) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid4-methyl-benzylamide

By proceeding in a manner similar to Example 246(a) above but using4-methylbenzylamine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid4-methyl-benzylamide (63.5 mg) as a white solid. MS: 382.54 (M+H)⁺. HPLC(Method B1): R_(T)=16.14 minutes.

(p) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

By proceeding in a manner similar to Example 246(a) above but using1-(3-aminopropyl)-2-pyrrolidinone there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide (68.1 mg) as a white solid. MS:401.13 (M−H)⁻. HPLC (Method B1): R_(T)=11.29 minutes.

(q) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-morpholin-4-yl-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using4-(2-aminoethyl)morpholine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-morpholin-4-yl-ethyl)-amide (70.8 mg) as a white solid. MS: 389.12(M−H)⁻. HPLC (Method B1): R_(T)=8.51 minutes.

(r) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-methoxy-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using2-methoxyethylamine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-methoxy-ethyl)-amide (55.2 mg) as a white solid. MS: 336.52 (M+H)⁺.HPLC (Method B1): R_(T)=11.30 minutes.

(s) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-cyano-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but heatingthe reaction at 50° C. and using 3-aminopropionitrile there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-cyano-ethyl)-amide (15.4 mg) as a white solid. MS: 331.15 (M+H)⁺,329.17 (M−H)⁻. HPLC (Method B1): R_(T)=12.72 minutes.

(t) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but heatingthe reaction at 50° C. and using 2-amino-2-methyl-1-propanol there wasprepared 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (29.6 mg) as a brown oil. LC-MS(Method L): R_(T)=10.57 minutes, 350.16 (M+H)⁺, 348.18 (M−H)⁻.

(u) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(3-imidazol-1-yl-propyl)-amide

By proceeding in a manner similar to Example 246(a) above but using1-(3-aminopropyl)imidazole there was prepared2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(3-imidazol-1-yl-propyl)-amide (31.9 mg) as a white solid. LC-MS (MethodB): R_(T)=8.45 minutes, 386.22 (M+H)⁺, 384.26 (M−H)⁻.

(v) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisobutyl-amide

By proceeding in a manner similar to Example 246(g) above but usingisobutylamine there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisobutyl-amide (101 mg) as a white solid. LC-MS (METHOD M): R_(T)=9.38minutes, 312 (M+H)⁺.

(w) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisopropylamide

By proceeding in a manner similar to Example 246(g) above but usingisopropylamine there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidisopropylamide (100 mg) as a white solid. LC-MS (METHOD L): R_(T)=7.21minutes, 298 (M+H)⁺.

(x) 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidcyclopropylmethyl-amide

By proceeding in a manner similar to Example 246(g) above but using(aminomethyl)cyclopropane there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidcyclopropylmethyl-amide (105 mg) as a white solid. LC-MS (METHOD M):R_(T)=8.77 minutes, 310 (M+H)⁺.

(y)3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid tert-butylamide

By proceeding in a manner similar to Example 246(j) above but usingtert-butylamine there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylicacid tert-butylamide (57 mg) as an off-white solid. LC-MS (METHOD M):R_(T)=13.86 minutes, 326 (M+H)⁺.

(z) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic aciddimethylamide dihydrochloride

By proceeding in a manner similar to Example 246(j) above, but (i) using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid [97mg, Example 263] and dimethylamine hydrochloride (23 mg), (ii) carryingout the reaction at ambient temperature overnight, and (iii) subjectingthe reaction product to flash column chromatography [eluting with ethylacetate to ethyl acetate/methanol (97:3, v/v)] followed by treatmentwith 4M hydrogen chloride in 1,4-dioxane and trituration withdichloromethane and diethyl ether there was prepared3(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic aciddimethylamide dihydrochloride (8 mg) as a white solid. LC-MS (METHOD M):R_(T)=9.37 minutes, 320 (M+H)⁺.

(aa)2-(4-Isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid benzylamide

By proceeding in a manner similar to Example 246(a) above but using2-(4-isobutylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[Reference Example 35] and benzylamine there was prepared2-(4-Isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid benzylamide (17 mg) as a white solid. LC-MS (METHOD L): R_(T)=11.00minutes, 403 (M+H)⁺.

(ab) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-piperidin-1-yl-ethyl)-amide

By proceeding in a manner similar to Example 246(a) above but using1-(2-aminoethyl)piperidine, and heating the reaction mixture at 50° C.for 6 hours, there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(2-piperidin-1-yl-ethyl)-amide as an oil. MS: 387.22 (M−H)⁻. HPLC(Method L): R_(T)=5.03 minutes.

(ac) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(pyridin-2-ylmethyl)-amide

By proceeding in a manner similar to Example 246(ab) above but using(2-aminomethyl)pyridine there was prepared2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid(pyridin-2-ylmethyl)-amide as an off-white solid. MS: 367.28 (M+H)⁺.HPLC (Method B1): R_(T)=9.33 minutes.

(ad) 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[3-(4-methyl-piperazin-1-yl)-propyl]-amide

By proceeding in a manner similar to Example 246(ab) above but using443-(aminopropyl))-1-methyl piperazine there was prepared2-(4H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[3-(4-methyl-piperazin-1-yl)-propyl]-amide as an oil. MS: 416.21 (M+H)⁺.HPLC (Method L): R_(T)=4.46 minutes.

(ae) N-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide

By proceeding in a manner similar to Example 246(ab) above but usingisobutyric acid and 2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine[Example 265] there was preparedN-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide as anoff-white solid. MS: 320.23 (M+H)⁺. HPLC (Method B1): R_(T)=19.28minutes.

EXAMPLE 247 (a) [2-(Indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid

A stirred solution of3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole [84.5 mg,Example 235(ac)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 mL)and water (2 mL) was heated at 75° C. overnight. The reaction mixturewas evaporated and the oily residue was partitioned between ethylacetate and water. The aqueous layer was acidified to pH 6 and extractedwith ethyl acetate. The organic layers was dried over magnesium sulfateand then evaporated to give[2{indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid (80 mg) as anoil. MS: 279.14 (M+H)⁺. HPLC (METHOD H): R_(T)=2.81 minutes.

(b) 3-(5,6-Dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid

By proceeding in a manner similar to Example 247(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid ethylester [Example 235(ae)] and carrying out the reaction at 60° C. therewas prepared3-(5,6-dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid as awhite solid. LC-MS (METHOD B): R_(T)=2.17 minutes; 257 (M+H)⁺.

(c)2-(4-Isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid

By proceeding in a manner similar to Example 247(a) above but using2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid methyl ester [Example 235(af)], replacing the tetrahydrofuran withmethanol and carrying out the reaction at 65° C., there was prepared2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid as a pale brown solid which was used without further purification.LC-MS (METHOD B): R_(T)=2.67 minutes; 314 (M+H)⁺.

(d)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid

By proceeding in a manner similar to Example 247(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid ethyl ester [Example 235(ag)], replacing the tetrahydrofuran withmethanol and carrying out the reaction at 65° C., there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylicacid as a white solid. LC-MS (METHOD B): R_(T)=2.75 minutes; 271 (M+H)⁺.

EXAMPLE 248 (a)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide

A stirred solution of5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [83 mg, Example233(c)] and diisopropylethylamine (256 μL) in dichloromethane (4 mL) wastreated with isobutyryl chloride (115 μL). The reaction mixture wasstirred for 30 minutes at room temperature then treated with piperidine(500 μL) and stirring was continued for a further hour. The reactionmixture was partitioned between 5% citric acid. The organic layer wasdried over magnesium sulfate and then evaporated. The residue wassubjected to flash chromatography on silica eluting with a mixture ofhexane and ethyl acetate to giveN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide(49 mg) as a white solid. MS: 298.28 (M+H)⁺. HPLC (METHOD B1):R_(T)=14.66 minutes.

(b)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide

By proceeding in a manner similar to Example 248(a) above but usingisovaleryl chloride there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramideas a white solid. MS: 312.28 (M+H)⁺. HPLC (METHOD B1): R_(T)=15.28minutes.

(c)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide

By proceeding in a manner similar to Example 248(a) above but usingphenylacetyl chloride there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamideas a white solid. LC-MS (METHOD B): R_(T)=2.83 minutes, 346.18 (M+H)⁺.

(d) Cyclopropanecarboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingcyclopropanecarbonyl chloride, there was prepared cyclopropanecarboxylicacid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 296.28 (M+H)⁺. HPLC (METHOD B1): R_(T)=13.50 minutes.

(e) Methoxyacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingmethoxyacetyl chloride, there was prepared methoxyacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 300.33 (M+H)⁺. HPLC (METHOD C1): R_(T)=14.25 minutes.

(f) Cyclopentanecarboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingcyclopentylcarbonyl chloride, there was prepared cyclopentanecarboxylicacid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 324.39 (M+H)⁺. HPLC (METHOD B1): R_(T)=17.64 minutes.

(g) Trimethylacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingtrimethylacetyl chloride, there was prepared trimethylacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 312.39 (M+H)⁺. HPLC (METHOD B1): R_(T)=19.52 minutes.

(h) tert-Butylacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingtert-butylacetyl chloride, there was prepared tert-butylacetic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 326.29 (M+H)⁺. HPLC (METHOD B1): R_(T)=19.52 minutes.

(i) Butanoic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingbutyryl chloride, there was prepared butanoic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 298.34 (M+H)⁺. HPLC (METHOD B1): R_(T)=15.07 minutes.

(j) Isoxazole-5-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingisoxazole-5-carbonyl chloride, there was prepared isoxazole-5-carboxylicacid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 323.16 (M+H)⁺. HPLC (METHOD B1): R_(T)=10.01 minutes.

(k) S(+)-2-Methylbutanoic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but usingS(+)-2-methyl butyryl chloride, there was prepared S(+)-2-methylbutanoicacid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 312.18 (M+H)⁺. HPLC (METHOD B1): R_(T)=11.15 minutes.

(l) Cyclopropanecarboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [Example233(d)] and cyclopropanecarbonyl chloride, there was preparedcyclopropanecarboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide as awhite solid. MS: 310.32 (M+H)⁺. HPLC (METHOD B1): R_(T)=8.88 minutes.

(m) Piperidine-1-carboxylicacid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but (i)treating a solution of3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [0.2g, Example 233(e)] and diisopropylethylamine (392 mg, 4 eq) intetrahydrofuran (25 mL) with piperidinecarbonyl chloride (450 mg, 4 eq),stirring overnight at ambient temperature, and evaporating the reactionmixture, (ii) triturating the reaction product with water (30 mL) andethyl acetate (50 mL) and extracting with aqueous layer with ethylacetate, (iii) combining the organic phases, drying over magnesiumsulfate, then evaporating (iv) chromatographing the residue on silicagel (ethyl acetate), (v) triturating the partially purified materialwith ethyl acetate (15 mL) for 1.5 hours and filtering, and (vi)evaporating the filtrate and chromatographing the residue on silica gel(ethyl acetate/heptane gradient of 20-0%) there was preparedpiperidine-1-carboxylicacid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide(50 mg) as a yellow solid, mp>310° C. LC-MS (Method E) R_(T)=3.25minutes, 374 (M+H)⁺.

(n)3-[3-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea

By proceeding in a similar manner to Example 248(m) above but usingN,N-dimethylcarbamyl chloride there was prepared3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylureaas a yellow solid, mp>300° C. LC-MS (Method E): R_(T)=2.4 minutes, 335(M+H)⁺.

(o) Cyclopropanecarboxylic acid[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [282 mg,Example 233(f)] and cyclopropanecarbonyl chloride (0.558 ml) there wasprepared cyclopropanecarboxylic acid[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (76 mg) asan off-white solid. LC-MS (Method L): R_(T)=5.25 minutes, 298.26 (M+H)⁺.

(p) Cyclopropanecarboxylic acid[3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(o) above but using3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [187 mg, Example233(g)] there was prepared cyclopropanecarboxylic acid[3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (112 mg) as apale yellow solid. LC-MS (Method H): R_(T)=2.26 minutes, 312.23 (M+H)⁺,310.30 (M−H)⁻.

(q) Cyclopropanecarboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-y)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(h)] and cyclopropanecarbonyl chloride there was preparedcyclopropanecarboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (135mg) as a white solid. LC-MS (METHOD M): R_(T)=11.31 minutes, 300.31(M+H)⁺.

(r) Cyclopropanecarboxylic acid[3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(i)] and cyclopropanecarbonyl chloride there was preparedcyclopropanecarboxylic acid[3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide(275 mg) as a white solid. LC-MS (METHOD M): R_(T)=13.57 minutes, 352.22(M+H)⁺.

(s) Cyclopropanecarboxylic acid[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(j)] and cyclopropanecarbonyl chloride there was preparedcyclopropanecarboxylic acid[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (88mg) as a white solid. LC-MS (METHOD M): R_(T)=13.62 minutes, 338.12(M+H)⁺.

(t)N-[3-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide

By proceeding in a manner similar to Example 248(s) above but usingisobutyryl chloride there was preparedN-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide(71 mg) as a white solid. LC-MS (METHOD M): R_(T)=10.11 minutes, 336.12(M+H)⁺.

(u) Cyclopropanecarboxylic acid[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 261] and cyclopropanecarbonyl chloride there was preparedcyclopropanecarboxylic acid[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (46mg) as a white solid. LC-MS (METHOD L): R_(T)=7.06 minutes, MS: 316.26(M+H)⁺.

(v) 3,5-Dimethyl-isoxazole-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248(a) above but using3,5-dimethylisoxazole-4-carbonyl chloride there was prepared3,5-dimethyl-isoxazole-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (62 mg)as a white solid. LC-MS (METHOD L): R_(T)=8.45 minutes, 351.32 (M+H)⁺.

(w) N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide

By proceeding in a manner similar to Example 248(a) above but usingacetyl chloride there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide (25mg) as a white solid. LC-MS (METHOD L): R_(T)=6.34 minutes, 270.14(M+H)⁺.

(x) Furan-3-carboxylic acid[3-(5,6-dimethylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 248 (a) above but using3-furoylchloride there was prepared furan-3-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (80 mg)as a white solid. LC-MS (METHOD L): R_(T)=7.10 minutes, 322.31 (M+H)⁺.

(y)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide

By proceeding in a manner similar to Example 248(a) above but usingp-toluoyl chloride there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide(42 mg) as a white solid. LC-MS (METHOD L): R_(T)=12.24 minutes, 346(M+H)⁺.

EXAMPLE 249 (a)5,6-Dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

A stirred solution of 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4,5-dimethylphenyl)amide [5.7 g, Reference Example 36(a)] inacetic acid (100 mL) was heated at 120° C. for 1 hour, then cooled toambient temperature and then evaporated. The oily residue waspartitioned between ethyl acetate and water. The organic layer was driedover magnesium sulfate and then evaporated to give5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (5.70 g) asan orange solid. LC-MS (METHOD B): R_(T)=2.30 minutes, 258.11 (M+H)⁺.

(b) 5-Ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-ethyl-5-methylphenyl)amide [Reference Example 36(b)] therewas prepared5-ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole as ayellow solid. LC-MS (METHOD B): R_(T)=2.61 minutes, 272.23 (M+H)⁺.

(c) 6-Chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-5-chloro-4-methoxyphenyl)amide [1.5 g, Reference Example 36(c)]there was prepared6-chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (0.7 g)as a dark solid. MS: 294 (M+H)⁺.

(d) 5-Fluoro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-fluoro-5-methyl-phenyl)-amide [Reference Example 36(f)] therewas prepared5-fluoro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (0.730g) as a red solid. LC-MS (METHOD J): R_(T)=2.76 minutes, 262.21 (M+H)⁺.

(e) 2-(4-Nitro-1H-pyrazol-3-yl)-5-trifluoromethoxy-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethoxy-phenyl)-amide [Reference Example 36(g)]there was prepared2-(4-nitro-1H-pyrazol-3-yl)-5-trifluoromethoxy-1H-benzoimidazole (1.02g) as a red solid. LC-MS (METHOD J): R_(T)=3.32 minutes, 314.19 (M+H)⁺.

(f) 2-(4-Nitro-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethyl-phenyl)-amide [Reference Example 36(h)] therewas prepared244-nitro-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole (0.195 g)as an orange solid. MS: 298.07 (M+H)⁺. HPLC (METHOD B): R_(T)=3.50minutes.

(g) 5-Chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 249(a) above but using4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-chloro-5-methyl-phenyl)-amide [Reference Example 36(i)] therewas prepared5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (0.320g) as an orange solid. LC-MS (METHOD C): R_(T)=3.36 minutes, 314.19(M+H)⁺.

(h) 2-(4-Nitro-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acidmethyl ester

By proceeding in a manner similar to Example 249(a) above but using3-amino-4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-benzoic acid methylester [Reference Example 36(j)] there was prepared2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylester (2.50 g) as a yellow solid. LC-MS (METHOD B): R_(T)=2.76 minutes,288.12 (M+H)⁺.

EXAMPLE 250 (a)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide

A solution of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[0.150 g, Example 251(a)] in dimethyl formamide (4 ml) was treated withdiisopropylethylamine (0.54 ml) and then with dimethyl carbamyl chloride(0.122 ml). After stirring for 1 hour the reaction mixture was quenchedby the addition of methanol (0.1 ml) and then diluted with ethylacetate. This mixture was washed five times with brine and thenevaporated. The residue was treated with tetrahydrofuran (9 ml) andmethanol (3 ml) and the resulting solution was then treated withpotassium hydroxide (50 mg). This mixture was stirred for 1 hour, thenacidified by addition of hydrochloric acid (1M) and then extracted threetimes with ethyl acetate. The aqueous layer was basified by addition ofsodium carbonate and the resulting suspension was filtered, then washedwith water, then dried in air and then azeotroped with toluene to yield3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide as a pale brown solid. MS: 339 (M+H)⁺. HPLC (METHODF1): R_(T)=8.67 minutes.

(b)Cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone

By proceeding in a manner similar to Example 250(a) above, but usingcyclopropanecarbonylchloride and stirring the reaction mixture for 16hours, there was preparedcyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone(68 mg) as a pale yellow solid. LC-MS (METHOD M): R_(T)=10.57 minutes,336 (M+H)⁺.

(c)Isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone

By proceeding in a manner similar to Example 250(b) above, but usingisopropylcarbonyl chloride, cyclopropylcarbonylchloride there waspreparedisopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone(68 mg) as a white solid. LC-MS (METHOD M): R_(T)=9.28 minutes, 338(M+H)⁺.

(d)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one

By proceeding in a manner similar to Example 250(b) above, but usingtrimethylacetyl chloride and filtering the precipitate formed uponbasification with sodium carbonate, followed by azeotroping with toluenethere was prepared1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one(49 mg) as a pale yellow solid. LC-MS (METHOD M): R_(T)=11.39 minutes,352 (M+H)⁺.

(e)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methyl ester

By proceeding in a manner similar to Example 250(b) above but usingmethylchloroformate there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methyl ester (89 mg) as a pale brown solid. LC-MS (METHOD M):R_(T)=8.95 minutes, 326 (M+H)⁺.

EXAMPLE 251 (a)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A solution of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [1.014 g, Example 252(a)] in methanol (20 ml) wastreated with a solution of hydrogen chloride in dioxane (5 ml, 4M).After stirring for 16 hours the reaction mixture was evaporated. Theresulting beige solid was triturated with methanol to yield3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(0.523 g) as a pale yellow solid. LC-MS (METHOD B): R_(T)=0.63 minutes;268 (M+H)⁺.

(b)3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

By proceeding in a manner similar to Example 251(a) above, but using3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Example 252(d)] there was prepared3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(223 mg) as a white solid. LC-MS (METHOD K): R_(T)=3.91 minutes, 288/290(M+H)⁺.

(c)3-[5-(2-Morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

By proceeding in a manner similar to Example 251(a) above, but using3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Example 252(e)] there was prepared3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(200 mg) as an off-white solid. LC-MS (METHOD N): R_(T)=2.55 minutes,369.19 (M+H)⁺.

(d)3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

By proceeding in a manner similar to Example 251(a) above but using3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Example 252(g)] there was prepared3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(500 mg) as an off-white solid. LC-MS (METHOD N): R_(T)=3.21 minutes,308.17 (M+H)⁺.

EXAMPLE 252 (a)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

A suspension of1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid,3-(2-amino-4,5-dimethylphenyl)amide, 5-tert-butyl ester [1.091 g,Reference Example 39(a)] in acetic acid (5 ml) was heated to 100° C. for12 minutes in a Smith Creator Microwave. The mixture was neutralisedwith care by addition of solid sodium hydrogen carbonate and thenextracted twice with ethyl acetate. The combined extracts wereevaporated to yield3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester. LC-MS (METHOD B): R_(T)=2.79 minutes; 368 (M+H)⁺.

(b) 5-Methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 252(a) above but (i) using4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl)-amide[410 mg, Reference Example 36(d)] and heating at 120° C. for 5 minutes,(ii) pouring the reaction mixture into water, adjusting to pH14 with 2Nsodium hydroxide and filtering, and (iii) adjusting the pH of thefiltrate to 6 with 2N hydrochloric acid and collecting the precipitateby filtration, there was prepared5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (327 mg) as ayellow powder. LC-MS (Method H): R_(T)=1.61 minutes, 260.25 (M+H)⁺,258.26 (M−H)⁻.

(c) 5-Ethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a manner similar to Example 252(b) above but using4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl)-amide[824 mg, Reference Example 36(e)] there was prepared5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl-1H-benzoimidazole (407 mg) as alight brown powder. LC-MS (Method H): R_(T)=1.82 minutes, 274.26 (M+H)⁺,272.30 (M−H)⁻.

(d)3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Example 252(b) above, but using3-(2-amino-4-chloro-5-methyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Reference Example 39(c)] and heating at 110° C.for 15 minutes, there was prepared3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (391 mg) as a brown solid. LC-MS (METHOD J):R_(T)=3.53 minutes, 388 (M+H)⁺.

(e)3-[5-(2-Morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Example 252(b) above, but using3-[2-amino-4-(2-morpholin-4-yl-ethoxy)-phenylcarbamoyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Reference Example 39(d)] there was prepared3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (350 mg) as a brown solid. LC-MS (METHOD N):R_(T)=3.53 minutes, 469.24 (M+H)⁺.

(f)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole

By proceeding in a manner similar to Example 252(a) above but using1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid(2-amino-4,5-dimethyl-phenyl)-amide [Reference Example 39(e)] andbeating at 120° C. for 3 minutes there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole(49 mg) as a pale brown solid. MS: 269 (M+H)⁺. HPLC (METHOD C1):R_(T)=19.68 minutes.

(g)3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Example 252(a) above but using3-(2-amino-4-trifluoromethyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester [Reference Example 39(f)] there was prepared3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (950 mg) was prepared as a brown solid. LC-MS(METHOD N): R_(T)=3.90 minutes, 408 (M+H)⁺.

EXAMPLE 253 (a)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide

A stirred solution of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg,Example 233(c)] and diisopropylethylamine (307 μl) in dichloromethane(10 ml) was treated with chloroacetyl chloride (105 μl). The reactionmixture was stirred for 30 minutes at room temperature, then treatedwith morpholine (575 μl), then kept at room temperature overnight andthen evaporated. The oily residue was partitioned between ethyl acetateand water and the organic phase was washed with water, then dried overmagnesium sulfate and then evaporated. The residue was subjected toflash chromatography on silica eluting with ethyl acetate to give theN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide(49.9 mg) as an off-white solid. MS: 355.68 (M+H)⁺. HPLC (METHOD B1):R_(T)=8.28 minutes.

(b)2-Dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide

By proceeding in a manner similar to Example 253(a) above but usingdimethylamine hydrochloride there was prepared2-dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide(52 mg) as a white solid. LC-MS (METHOD M): R_(T)=8.28 minutes, 355.68(M+H)⁺.

(c)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide

By proceeding in a manner similar to Example 253(a) above but usingpiperidine there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide(4 mg) as a white solid. LC-MS (METHOD M): R_(T)=7.69 minutes, 353.68(M+H)⁺.

EXAMPLE 254 (a)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide

A stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (295.7 mg) and diisopropylethylamine (269 μl) indimethylformamide (10 ml) were treated with3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg,Example 233(c)] and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8mg). The reaction mixture was stirred for 72 hours then treated furtherwith 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7mg), diisopropylethylamine (269 μl) and 2-(1H-1,2,3,4-tetraazol-1-yl)acetic acid (197.8 mg). Stirring was continued for a further 48 hoursthen the reaction mixture was partitioned between ethyl acetate andwater. The organic phase was evaporated and the residue was treated with1N potassium hydroxide in a mixture of methanol and tetrahydrofuran(1:4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate.The extract was washed with brine, then dried over magnesium sulfate andthen evaporated to dryness. The residue was subjected to preparativeHPLC to giveN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide(13.7 mg) as an off-white solid. MS: 338.14 (M+H)⁺. HPLC (METHOD B1):R_(T)=7.26 minutes.

(b)N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide

By proceeding in a manner similar to Example 254(a) above but usingisonicotinic acid there was preparedN-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide(9 mg) as a white solid. LC-MS (METHOD L): R_(T)=8.71 minutes, 331.21(M+H)⁺.

(c)2-Cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide

By proceeding in a manner similar to Example 254(a) above but usingcyclopropylacetic acid there was prepared2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide(98 mg) as a light pink solid. LC-MS (METHOD M): R_(T)=11.04 minutes,MS: 310 (M+H)⁺.

EXAMPLE 255 (a)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea

A solution of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [0.500 g,Example 233(c)] in tetrahydrofuran (5 ml) was treated with methylisocyanate (0.502 ml) and the mixture stirred at ambient temperature for16 hours. The mixture was then concentrated in vacuo and the residue wasredissolved in 1N potassium hydroxide in a mixture of methanol andtetrahydrofuran (1:3, 5 ml). The mixture was stirred for a further 1hour, then concentrated and then partitioned between ethyl acetate andwater. The aqueous layer was extracted three times with ethyl acetateand the combined organic extracts were washed with brine, then driedover magnesium sulfate, and then evaporated. The residue was subjectedto flash column chromatography on silica eluting initially with amixture of ethyl acetate and hexane (1:1, v/v) and then with ethylacetate to afford1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl-1H-pyrazol-4-yl]-3-methyl-urea(230 mg) as a white solid. MS: 269 (M+H)⁺. HPLC (METHOD D1): R_(T)=5.97minutes.

(b)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea

By proceeding in a manner similar to Example 255(a) above but usingisopropyl isocyanate there was prepared1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-ureaas a white solid. MS: 313 (M+H)⁺. HPLC (METHOD D1): R_(T)=10.94 minutes.

(c)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea

By proceeding in a manner similar to Example 255(a) above but usingphenyl isocyanate there was prepared1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-ureaas a white solid. MS: 347 (M+H)⁺. HPLC (METHOD B1): R_(T)=16.16 minutes.

(d)1-Benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

By proceeding in a manner similar to Example 255(a) above but usingbenzyl isocyanate there was prepared1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-ureaas a white solid. MS: 361(M+H)⁺. HPLC (METHOD D1): R_(T)=7.78 minutes.

(e)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide

By proceeding in a manner similar to Example 255(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251(a)] and isopropylisocyanate, and subjecting the reactionproduct to flash column chromatography eluting with ethylacetate/methanol (19:1, v/v), there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide (93.3 mg) as an off-white solid. LC-MS (METHOD M):R_(T)=10.15 minutes, 353 (M+H)⁺.

EXAMPLE 256 (a) Cyclopropanecarboxylicacid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide

A solution of cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide[0.3 g, Reference Example 48(a)] and p-toluenesulfonic acid hydrate (1.2g) in ethanol (25 mL) was heated in an 80° C. in an oil bath for 1 hour,then cooled, and then poured into aqueous sodium bicarbonate solution.The aqueous mixture was extracted twice with ethyl acetate (75 mL). Thecombined extracts were evaporated and the residue was redissolved in amixture of methylene chloride (100 mL) and methanol (10 mL). Thissolution was washed with aqueous sodium bicarbonate, to remove someresidual p-toluenesulfonic acid, then evaporated to givecyclopropanecarboxylicacid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide(120 mg) as a white solid. LC-MS (Method E): R_(T)=2.36 minutes, 340(M+H)⁺.

(b) 3-(1,5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Example 256(a) but using3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine[0.9 g, Reference Example 49(d)] and p-toluenesulfonic acid (1.0 g) inethanol (100 mL) and carrying out the reaction at 55° C. for 2 hours,there was prepared3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine(800 mg) as a brown solid. LC-MS (Method G): R_(T)=2.68 minutes, 240(M+H)⁺.

(c) 4-Methylpiperazine-1-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Example 256(a) but (i) using4-methylpiperazine-1-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide[171 mg, Reference Example 48(b)], (ii) carrying out the reaction at 55°C. for 1.5 hours, then at 70° C. for 1 hour, and (iii) subjecting thereaction product to chromatography on silica gel (ethyl acetate/gradient0 to 20% methanol), there was prepared 4-methylpiperazine-1-carboxylicacid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide(55 mg) as a white solid. LC-MS (Method E): R_(T)=1.53 minutes, 366(M+H)⁺.

(d)1,1-Dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea

By proceeding in a similar manner to Example 256(c) but using1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea(230 mg) and p-toluenesulfonic acid hydrate [40 mg, Reference Example48(c)] there was prepared1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea(106 mg) as a tan solid. LC-MS (Method E): R_(T)=1.97 minutes, 311(M+H)⁺.

EXAMPLE 257 (a) Cyclopropanecarboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide

A solution of cyclopropanecarboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide[90 mg, Reference Example 48(d)] in a 1/1 mixture of trifluoroaceticacid and dichloromethane (30 mL) was stirred for 5 hours and thenevaporated. The residue was mixed with ethyl acetate (30 mL) and aqueoussodium bicarbonate (30 mL). The organic layer was evaporated to givecyclopropanecarboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide (44mg). LC-MS (Method E): R_(T)=2.34 minutes, 330 (M+H)⁺.

(b) Tetrahydropyran-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide

By proceeding in a similar manner to Example 257(a) but usingtetrahydropyran-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazole-4-yl]amide[120 mg, Reference Example 48(e)] there was preparedtetrahydropyran-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide (65mg). LC-MS (Method E) R_(T)=2.17 minutes, 374 (M+H)⁺.

(c) Morpholine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Example 257(a) but usingmorpholine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide[140 mg, Reference Example 48(f)] there was preparedmorpholine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide(65 mg). LC-MS (Method E): R_(T)=2.62 minutes, 375 (M+H)⁺.

(d) Piperidine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Example 257(a) but usingpiperidine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide[127 mg, Reference Example 48(g)] there was preparedpiperidine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide(65 mg). LC-MS (Method E): R_(T)=3.15 minutes. MS 373 (M+H)⁺.

(e)3-[6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl-1H-pyrazol-4-yl]-1-diethylurea

By proceeding in a similar manner to Example 257(a) but using3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl)-1,1-diethylurea(110 mg, Reference Example 48(h)] there was prepared3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1H-diethylurea(65 mg). LC-MS (Method E): R_(T)=3.13 minutes, 361 (M+H)⁺.

(f) 5-Methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole

By proceeding in a similar manner to Example 257(a) but using5-methoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole(282 mg, Reference Example 50(d) there was prepared5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole (373 mg) as ared powder. LC-MS (Method H): R_(T)=1.60 minutes, 260.22 (M+H)⁺, 258.23(M−H)⁻.

(g) Morpholine-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide

By proceeding in a similar manner to Example 257(a) but usingmorpholine-4-carboxylic acid(2,4-dimethoxy-benzyl)-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylmethyl]-amide(Reference Example 59), subjecting the reaction product to flashchromatography on silica [eluting with dichloromethane todichloromethane/methanol (9:1)] and recrystallising fromwater/acetonitrile followed by trituration with diethyl ether there wasprepared morpholine-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide(16.5 mg) as a white solid. LC-MS (Method M): R_(T)=6.97 minutes, MS:355.36 (M+H)⁺, 353.39 (M−H)⁻.

(h)3-[3-(5-Difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea

By proceeding in a manner similar to Example 257(a) above but using3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea[Reference Example 48(j)] there was prepared3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea(60 mg) as a white solid. LC-MS (METHOD L): R_(T)=10.61 minutes. ¹HNMR(CD₃OD): δ 1.24 (t, 6H), 3.43 (q, 4H), 6.72 (bt, 1H), 6.98 (d, 1H),7.26 (s, 1H), 7.47 (d, 1H), 7.91 (s, 1H).

(i) Piperidine-1-carboxylic acid[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 257(a) above but usingpiperidine-1-carboxylic acid[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-amide[Reference Example 48(k)], there was prepared piperidine-1-carboxylicacid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide(52 mg) as a white solid. HPLC (METHOD E1): R_(T)=10.78 minutes. ¹HNMR(CD₃OD): δ 1.69 (bm, 6H), 3.64 (bm, 4H), 6.82 (bt, 1H), 7.09 (bm,1H), 7.39 (bm, 1H), 7.61 (bm, 1H), 8.05 (bm, 1H).

EXAMPLE 258 (a) Cyclopropanecarboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

A solution of3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [50mg, Example 233(e)] and diisopropylethylamine (40 μL) in dichloromethane(20 mL), stirred at room temperature, was treated withcyclopropanecarbonyl chloride (51 μL, 3 eq). After stirring for afurther 20 hours the reaction mixture was evaporated and the residue wassubjected to chromatography on silica gel (ethyl acetate/heptane 1/1) togive the bis-acylated product (60 mg) as an orange solid. MS 400 (M+H)⁺.The bis-acylated product was dissolved in methanol (5 mL), then treatedwith potassium hydroxide solution (0.5 mL, 5N), then stirred at 60° C.for 1 hour, then cooled and then evaporated. The residue was treatedwith water (15 mL) and the pH of the aqueous mixture was adjusted to 5and then extracted twice with ethyl acetate (25 mL). The combinedextracts were dried with magnesium sulfate, then evaporated and theresidue was triturated with diisopropyl ether, filtered and theprecipitate was vacuum dried at 60° C. to give cyclopropanecarboxylicacid [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl-1H-pyrazol-4-yl]-amide(11 mg) as an off-white solid, mp 225-226° C. LC-MS (Method E):R_(T)=2.92 minutes, 332 (M+H)⁺.

(b) Cyclopropanecarboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Example 258(a) above but (i)treating a solution of3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine[310 mg, Example 256(b)] and triethylamine (4 eq) in tetrahydrofuran (15mL) with cyclopropanecarbonyl chloride (4 eq), (ii) stirring thereaction mixture at 60° C. for 2 hours, (iii) treating the resultingbis-acylated product with methanolic potassium hydroxide (20 mL, 10.05 gKOH) at 40° C. for 1 hour followed by treatment with aqueous ammoniumchloride (200 mL), (iii) extracting this mixture three times with ethylacetate (100 mL), (iv) evaporating the combined extracts and (v)chromatographing the residue on silica gel (ethyl acetate/gradient of50-0% heptane) there was prepared cyclopropanecarboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide(50 mg) as a yellow solid. LC-MS (Method E) R_(T)=2.05 minutes, 308(M+H)⁺.

(c) Morpholine-4-carboxylicacid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a similar manner to Example 258(b) above but usingmorpholine-4-carbonyl chloride there was preparedmorpholine-4-carboxylicacid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amideas an orange solid. LC-MS (Method E) R_(T)=2.45 minutes, 353 (M+H)⁺.

(d) Piperidine-1-carboxylic acid[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a similar manner to Example 258(a) above treating3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [257 mg,Example 233(f)] with 1-piperidine-carbonyl chloride in the presence ofdiisopropylethylamine and using tetrahydrofuran as the solvent there wasprepared piperidine-1-carboxylic acid[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (46.1 mg) asa white solid. LC-MS (Method L) R_(T)=6.43 minutes, 341.28 (M+H)⁺.

(e)3-[3-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea

By proceeding in a manner similar to Example 258(d) above but usingdimethylcarbamyl chloride there was prepared3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-ureaas a white solid. LC-MS (Method M): R_(T)=7.64 minutes, 301.35 (M+H)⁺.

(f) Piperidine-1-carboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 258(d) above but (i) using3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [400 mg,Example 233(d)], 1-piperidinecarbonyl chloride (1.25 ml) anddiisopropylethylamine (1.74 ml) with tetrahydrofuran (20 ml) as thesolvent and, stirring the reaction mixture at ambient temperature for 48hours, then at 50° C. for 24 hours, (ii) treating the bis-acylatedproduct with 1M potassium hydroxide in methanol/tetrahydrofuran (1:3, 20ml) at room temperature, and (iii) subjecting the product to flashcolumn chromatography on silica [eluting with ethyl acetate/hexane (1:1v/v) to ethyl acetate/hexane (3:1 v/v)], there was preparedpiperidine-1-carboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (425mg) as a white solid. LC-MS (METHOD L): R_(T)=7.55 minutes, 353.34(M+H)⁺.

(g)3-[3-(5-Fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea

By proceeding in a manner similar to Example 258(f) above but using3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(h)] and N,N′-dimethylcarbamylchloride there was prepared3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea(32 mg) as a white solid. LC-MS (METHOD M): R_(T)=10.40 minutes, 303.34(M+H)⁺.

(h) Morpholine-4-carboxylic acid[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 258(f) above but using3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(j)] and morpholine-1-carbonyl chloride there was preparedmorpholine-4-carboxylic acid[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (131mg) was prepared as a white solid. MS: 379.08 (M−H)⁻. HPLC (METHOD E1):R_(T)=10.61 minutes.

(i)3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide

By proceeding in a manner similar to Example 258(f) above, but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251(a)] and diethylcarbamyl chloride, and subjecting thereaction product to flash column chromatography eluting with ethylacetate to ethyl acetate/methanol (49:1, v/v), there was prepared3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide (20.9 mg) as an off-white solid. LC-MS (METHOD J):R_(T)=3.44 minutes, 367 (M+H)⁺.

(j)[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]pyrrolidin-1-yl-methanone

By proceeding in a manner similar to Example 258(i) above, but using1-pyrollidincarbonyl chloride and triturating the reaction product withethyl acetate, methanol and dichloromethane, there was prepared[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone(68 mg) as an off-white solid. MS: 365 (M+H)⁺. HPLC (METHOD E1):R_(T)=10.32 minutes.

(k)[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone

By proceeding in a manner similar to Example 258(f) above, but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251(a)] and subjecting the reaction product to flash columnchromatography eluting with ethyl acetate/petrol (5:1, v/v) to 100%ethyl acetate to ethyl acetate/methanol (19:1, v/v), there was prepared[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone(93.3 mg) as an off-white solid. LC-MS (METHOD L): R_(T)=6.77 minutes,379 (M+H)⁺.

(l)[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone

By proceeding in a manner similar to Example 258(k) above, but using1-morpholinecarbonyl chloride and azeotroping the reaction product withtoluene and dichloromethane, there was prepared[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone(32 mg) as an off-white solid. MS: 381 (M+H)⁺. HPLC (METHOD E1):R_(T)=9.39 minutes.

(m)3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide

By proceeding in a manner similar to Example 258(a) above but (i) using3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251(b)) and diethylcarbamyl chloride, and (ii) subjecting thereaction product to flash column chromatography, eluting with ethylacetate to ethyl acetate/methanol (47:3, v/v) followed by triturationwith ethanol, there was prepared3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide (35.6 mg) as a pale yellow solid. MS: 387/389 (M+H)⁺.HPLC (METHOD E1): R_(T)=11.07 minutes.

(n) Morpholine-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-y)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 258(p) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [Example233(c)] and 1-morpholinecarbonyl chloride there was preparedmorpholine-4-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (206 mg)as a white solid. LC-MS (METHOD L): R_(T)=7.36 minutes, 341 (M+H)⁺.

(o) Piperidine-1-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 258(p) above but using1-piperidinecarbonyl chloride there was prepared piperidine-1-carboxylicacid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (185mg) as a white solid. LC-MS (METHOD M): R_(T)=10.79 minutes, 339 (M+H)⁺.

(p) 3-[5-(2-Morpholin-4-yl-ethoxy) IH-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide

By proceeding in a manner similar to Example 258(a) above but using3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251 (c)] and diethylcarbamyl chloride there was prepared3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide (28 mg) as a white solid. MS: 468.30 (M+H)⁺. HPLC(METHOD E1): R_(T)=9.47 minutes.

(q)3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide

By proceeding in a manner similar to Example 258(a) above but using3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine[Example 251(d)] and diethylcarbamyl chloride there was prepared3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid diethylamide (103 mg) as a white solid. MS: 407.17 (M+H)⁺. HPLC(METHOD E1): R_(T)=10.81 minutes.

(r)3-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea

By proceeding in a manner similar to Example 258(p) above but usingdimethylcarbamyl chloride there was prepared3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl-1,1-dimethyl-urea.MS: 299 (M+H)⁺. HPLC (Method E1): R_(T)=8.24 minutes.

EXAMPLE 259 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[2-(2H-tetrazol-5-yl)-ethyl]-amide

A stirred solution of 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (2-cyano-ethyl)-amide [150 mg, Example 246(s)] and azidotributyltin(2 ml) was heated at 95° C. for 24 hours. The reaction was cooled toambient temperature and stirred for 2 hours with acetonitrile (20 ml),tetrahydrofuran (10 ml) and acetic acid (20 ml). The reaction mixturewas washed with iso-hexane (6×80 ml) and concentrated in vacuo. Theresidue was subjected to preparative HPLC to give2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid[2-(2H-tetrazol-5-yl)-ethyl]-amide (35.9 mg) as a brown solid.

LC-MS (Method L): R_(T)=9.80 minutes, 374.21 (M+H)⁺.

EXAMPLE 260 (a)1-Cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

To a stirred solution of3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [250 mg,Example 233(d)] in tetrahydrofuran (20 ml) was added1,1-carbonyldiimidazole (740 mg) and the reaction heated at reflux for60 hours. The reaction mixture was cooled to ambient temperature and thesolvent removed in vacuo. The residue was added 2M cyclopropylamine intetrahydrofuran (15 ml). The reaction mixture was transferred to apressure tube and heated at reflux for 48 hours. The reaction mixturewas cooled to ambient temperature and partitioned between ethyl acetateand water. The aqueous layer was extracted three times with ethylacetate and the combined organic extracts washed with brine, dried overmagnesium sulfate, and concentrated. The residue was subjected to flashcolumn chromatography on silica eluting with ethyl acetate/hexane (1:1v/v) to 100% ethyl acetate to afford1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea(95 mg) as a white solid. LC-MS (METHOD M): R_(T)=9.40 minutes, 325.32(M+H)⁺.

(b)1-[3-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea

By proceeding in a manner similar to Example 260(a) above but using 2Mmethylamine in tetrahydrofuran there was prepared1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea(36 mg) as a white solid. LC-MS (METHOD M): R_(T)=7.08 minutes, 299.34(M+H)⁺.

(c) 4-Methyl-piperazine-1-carboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 260(a) above but using 2M1-methylpiperazine in tetrahydrofuran there was prepared4-methyl-piperazine-1-carboxylic acid[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (247mg) pared as a white solid. LC-MS (METHOD M): R_(T)=5.21 minutes, 368.32(M+H)⁺.

(d) Piperidine-1-carboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 260(a) above but using3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 233(h)] and 2M piperidine in tetrahydrofuran there was preparedpiperidine-1-carboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (140mg) as a white solid. LC-MS (METHOD L): R_(T)=8.29 minutes, 343.26(M+H)⁺.

(e)1-[3-(5-Fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea

By proceeding in a manner similar to Example 260(d) above but using 2Mmethylamine in tetrahydrofuran there was prepared1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea(61 mg) as a white solid. LC-MS (METHOD L): R_(T)=4.85 minutes, 289.26(M+H)⁺.

(f) Morpholine-4-carboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 260(d) above but using 2Mmorpholine in tetrahydrofuran there was prepared morpholine-4-carboxylicacid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide(49 mg) as a white solid. LC-MS (METHOD L): R_(T)=6.26 minutes, 345.33(M+H)⁺.

(g) 4-Methyl-piperazine-1-carboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl]-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 31(d) above but using 2M1-methylpiperazine in tetrahydrofuran there was prepared4-methyl-piperazine-1-carboxylic acid[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (58mg) as a white solid. LC-MS (METHOD P): R_(T)=7.72 minutes, 358.19(M+H)⁺.

(h)1-Methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

By proceeding in a manner similar to Example 260(a) above but using3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 2330)] and 2M methylamine in tetrahydrofuran there was prepared1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl1-urea (99 mg) as a white solid. LC-MS (METHOD L): R_(T)=6.51 minutes,325 (M+H)⁺.

(i)1-[3-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea

By proceeding in a manner similar to Example 260(a) above but using3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine[Example 261] and 2M methylamine in tetrahydrofuran there was prepared1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl]-1H-pyrazol-4-yl]-3-methyl-urea(45 mg) as a white solid. LC-MS (METHOD L): R_(T)=5.85 minutes, 305/307(M+H)⁺.

(j) 4-Methyl-piperazine-1-carboxylic acid[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 260(i) above but using 2M1-methylpiperazine in tetrahydrofuran there was prepared4-methyl-piperazine-1-carboxylic acid[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (60mg) as a pale yellow solid. LC-MS (METHOD M): R_(T)=6.35 minutes, 374(M+H)⁺.

(k)1-tert-Butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

By proceeding in a manner similar to Example 260(a) above but using3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [Example233(c)] and tert-butylamine there was prepared1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea(21 mg) as a white solid. LC-MS (METHOD L): R_(T)=5.38 minutes, 327(M+H)⁺.

(l)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea

By proceeding in a manner similar to Example 260(k) above but using 2Methylamine in tetrahydrofuran there was prepared1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea(39 mg) as a white solid. LC-MS (METHOD L): R_(T)=3.95 minutes, 299(M+H)⁺.

(m) 4-Methyl-piperazine-1-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Example 260(k) above but using 2M1-methylpiperazine in tetrahydrofuran there was prepared4-methyl-piperazine-1-carboxylic acid[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (113 mg)as a white solid. MS: 354 (M+H)⁺. HPLC (METHOD E1): R_(T)=10.21 minutes.

(n)1-Cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

By proceeding in a manner similar to Example 260(k) above but usingcyclopropylamine there was prepared1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea(80 mg) as a white solid. MS: 311 (M+H)⁺. HPLC (METHOD E1): R_(T)=10.36minutes.

(o)3-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea

By proceeding in a manner similar to Example 260(k) above but using 2Mdiethylamine in tetrahydrofuran there was prepared3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea(61 mg) as a white solid. MS: 327 (M+H)⁺. HPLC (METHOD E1): R_(T)=11.36minutes.

(p)1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea

By proceeding in a manner similar to Example 2601(k) above but using 2Misobutylamine in tetrahydrofuran, there was prepared1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea(58 mg) as a white solid. MS: 327 (M+H)⁺. HPLC (METHOD E1): R_(T)=10.95minutes.

(q)1-Cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea

By proceeding in a manner similar to Example 260(k) above but using 2M(aminomethyl)cyclopropane in tetrahydrofuran, there was prepared1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea(29 mg) as a white solid. MS: 325 (M+H)⁺. HPLC (METHOD E1): R_(T)=10.63minutes.

EXAMPLE 2613-(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine

A stirred solution of5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [0.320g, Example 249(g)] and tin-chloride (1.10 g) in ethanol (5 ml) washeated in a Smith Creator microwave at 140° C. for 10 minutes. Thereaction mixture was basified using saturated sodium hydrogen carbonatesolution to pH 8 and extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate and concentrated to give3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine as apale brown solid. LC-MS (METHOD B): R_(T)=2.28 minutes, 248.13 (M+H)⁺.

EXAMPLE 2623-(5-Ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acidamide dihydrochloride

A stirred suspension of3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile[100 mg, Example 235(an)] in acetic acid (1 ml) and concentratedhydrochloric acid (1 ml) was heated at 80° C. for 30 minutes and then at100° C. for 4 hours. The reaction was cooled to ambient temperature andstirred for 16 hours. The reaction was then heated at 80° C. for 2.5hours and then at 100° C. for 2 hours. The reaction mixture was cooledto ambient temperature and neutralized with aqueous sodium carbonatesolution. The resulting white precipitate was collected by filtrationand the aqueous layer was extracted with ethyl acetate, combined withthe precipitate and concentrated in vacuo. The residue was taken up inmethanol, transferred to a solid phase cartridge containing MP-carbonateresin (100 mg) and shaken for 16 hours. The reaction was then filtered,the resin washed with methanol and the combined organic layersconcentrated in vacuo. The residue was triturated with diethyl ether,taken up in methanol and acidified with 4M hydrogen chloride in1,4-dioxane. The solvent was removed in vacuo to give3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acidamide dihydrochloride (58 mg) as a pale brown solid. LC-MS (METHOD M):R_(T)=9.40 minutes, 320(M+H)⁺.

EXAMPLE 2633-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid

A stirred suspension of3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitriledihydrochloride [200 mg, Reference Example 6(aq)] in aceticacid/concentrated hydrochloric acid (4 ml, 1:1 v/v) was heated at 100°C. for 16 hours. The reaction mixture was cooled to ambient temperatureand filtered. The precipitate was washed with water and dried in vacuoto give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylicacid (195 mg) as a white solid. LC-MS (METHOD B): R_(T)=2.52 minutes,307 (M+H)⁺.

EXAMPLE 2642-(4-Isobutyrylamino-1H-pyrazol-3-y)-1H-benzoimidazole-5-carboxylic acid

To a stirred solution of2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylester [200 mg, Example 233(k)] in tetrahydrofuran (5 ml) was addeddiisopropylethylamine (545 μl) and isobutyryl chloride (327 μl) dropwiseand the reaction stirred for 30 minutes. The reaction mixture wasconcentrated in vacuo and the residue was taken up in 1M potassiumhydroxide in tetrahydrofuran/methanol (1:3, v/v) (5 ml) and stirred for1 hour. The reaction mixture was concentrated in vacuo and the residuewas taken up in 1M sodium hydroxide in water/methanol (5 ml) and stirredfor 1 hour. The solvent was removed in vacuo and the residue waspartitioned between ethyl acetate and water and the layers separated.The aqueous layer was acidified to pH 3-4 with 5% citric acid solution,extracted with ethyl acetate and the organic layer washed with brine.The organic layer was then dried over magnesium sulfate, filtered andthe filtrate concentrated in vacuo to give2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylicacid (140 mg) as a white solid. LC-MS (METHOD C): R_(T)=2.87 minutes,313.33 (M+H)⁺.

EXAMPLE 265 2-(1H-Indazol-3-yl)-3H-benzoimidazol-5-amine

A stirred solution of 3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole[90.8 mg, Reference Example 233(as)] in methanol (1 ml) was treated withtin chloride (616 mg). The reaction was heated at reflux for 16 hoursand then cooled to ambient temperature. The pH of the reaction mixturewas adjusted to pH 8 by addition of aqueous sodium bicarbonate and thenthis mixture was extracted with ethyl acetate. The organic extracts weredried over magnesium sulfate and then evaporated to yield an oil. Thecrude product was subjected to flash column chromatography on silicaeluting with ethyl acetate and 10% triethylamine to give2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine (826 mg). MS: 250.31(M+H)⁺, 248.31 (M−H)⁻. HPLC (Method B): R_(T)=2.03 minutes.

REFERENCE EXAMPLE 1 (a)5,6-Dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl-1H-benzoimidazole

A mixture of1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone[318 mg, Reference Example 2(a)], hydrazine (2 mL) and ethanol (12 mL)was heated at reflux temperature for 1 hour. The reaction mixture wasthen cooled to room temperature, then stirred at room temperatureovernight, then heated at 60° C. for 2 hours, then heated at refluxtemperature for 3 hours, then stood at room temperature for 3 days andthen evaporated. The residue was dissolved in dichloromethane and thissolution was washed with water plus a little brine to facilitateseparation and the aqueous phase was washed with dichloromethane andthen with ethyl acetate. The combined organics were dried over magnesiumsulfate and then evaporated to give5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(90 mg) as a colourless solid.

(b) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone[Reference Example 2(b)] there was prepared6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(c) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-ethylsulfanyl-propenone[Reference Example 2(c)] there was prepared6-chloro-5-methyl-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

(d) By proceeding in a similar manner to Reference Example 1(a) abovebut using3,3-bis-methylsulfanyl-1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[Reference Example 2(d)] there was prepared2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

(e) By proceeding in a similar manner to Reference Example 1(a) abovebut using3,3-bis-cyclopropylmethylsulfanyl-1-[5,6-dimethyl-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[Reference Example 2(e)] there was prepared2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(f) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-ethylsulfanylpropenone [Reference Example 2(f)] there was prepared5,6-dimethyl-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(g) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-(pyridin-3-ylmethylsulfanyl)-propenone[Reference Example 2(g)] there was prepared5,6-dimethyl-2-(5-(pyridin-3-yl)methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(h) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone[Reference Example 2(h)] there was prepared5-fluoro-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(i) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-phenethylsulfanyl-propenone[Reference Example 2(i)] there was prepared5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(j) By proceeding in a similar manner to Reference Example 1(a) abovebut using3,3-bis-methylsulfanyl-1-[4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[Reference Example 2(k)] there was prepared4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(k) By proceeding in a similar manner to Reference Example 1(a) abovebut using3,3-bis-benzylsulfanyl-1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[Reference Example 2(o)] there was prepared2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(l) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3-methylsulfanyl-3-morpholin-1-yl-propenone[Reference Example 13] there was prepared6-chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(m) By proceeding in a similar manner to Reference Example 1(a) abovebut using1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-(thiophen-2-ylmethylsulfanyl)propenone [Reference Example 2(s)] there was prepared5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

REFERENCE EXAMPLE 2 (a)1-[5,6-Dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone

A stirred suspension of sodium tert-butoxide (350 mg) in benzene (6 mL),at −5° C., was treated with a solution of1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[240 mg, Reference Example 3(a)] in benzene (5 mL) followed by carbondisulfide (230 μL). The resulting orange solution was stirred for 1 hourat −5° C., then treated with methyl iodide (180 μL), then allowed towarm to room temperature and then stirred at room temperature overnight.An orange precipitate was formed. The reaction mixture was poured intoice-water and this mixture was then extracted with dichloromethane. Thecombined organic extracts were washed with water, then dried over sodiumsulfate and then evaporated to give1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone(318 mg) as an orange oil which was used without further purification.

(b) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(b)] there was prepared1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone.

(c) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(b)] and ethyl iodide there was prepared1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-ethylsulfanyl-propenone.

(d) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(c)] there was prepared3,3-bis-methylsulfanyl-1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone.

(e) By proceeding in a similar manner to Reference Example 2(a) abovebut using bromomethylcyclopropane there was prepared3,3-bis-cyclopropylmethylsulfanyl-1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone.

(f) By proceeding in a similar manner to Reference Example 2(a) abovebut using ethyl iodide there was prepared1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl-3,3-bis-ethylsulfanyl-propenone.

(g) By proceeding in a similar manner to Reference Example 2(a) abovebut using 3-picolyl chloride there was prepared1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-(pyridin-3-ylmethylsulfanyl)-propenone.

(h) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(d)] there was prepared1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone.

(i) By proceeding in a similar manner to Reference Example 2(a) abovebut using phenethyl bromide there was prepared1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-phenethylsulfanyl-propenone.

(j) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 4(g)] and ethyl bromide there was prepared3,3-bis-ethylsulfanyl-1-[5-methoxy-2-(trimethylsilanylethoxymethyl)-1H-benzoimidazol-2-yl]-propenone.

(k) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(e)] there was prepared3,3-bis-methylsulfanyl-1-[4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone.

(l) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-pentan-1-one[Reference Example 3(f)] there was prepared2-(bis-methylsulfanyl-methylene)-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one.

(m) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-pentan-1-one[Reference Example 3(f)] and 4-methoxybenzyl chloride there was prepared2-[bis-(4-methoxy-benzylsulfanyl)-methylene]-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one.

(n) By proceeding in a similar manner to Reference Example 2(a) abovebut using3-methyl-1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-one[Reference Example 3(g)] and benzyl chloride there was prepared2-(bis-benzylsulfanyl-methylene)-3-methyl-1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-one.

(o) By proceeding in a similar manner to Reference Example 2(a) abovebut using benzyl chloride there was prepared3,3-bis-benzylsulfanyl-1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone.

(p) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 4(h)] with tetrahydrofuran as the solvent andcarrying out the reaction at room temperature and then subjecting thereaction product to flash chromatography on silica under gradientelution conditions (20 to 33% ethyl acetate in pentane) there wasprepared3,3-bis-methanesulfanyl-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenoneas an oil which slowly solidified on standing at room temperature.

(q) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(b)] and methyl iodide there was prepared1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methylsulfanyl-propenone.

(r) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propan-1-one[Reference Example 4(i)] and methyl iodide there was prepared1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-2-methyl-3-(bis-methanesulfanyl)-1-propenone.

(s) By proceeding in a similar manner to Reference Example 2(a) abovebut using of1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone[Reference Example 3(a)] and 2-chloromethylthiophene [Reference Example14]) there was prepared1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-(thiophen-2-ylmethylsulfanyl)-propenone.

(t) By proceeding in a similar manner to Reference Example 2(a) abovebut using1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propan-1-one[Reference Example 3(h)] there was prepared1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-2-methyl-3-(bis-methanesulfanyl)-1-propenone.

REFERENCE EXAMPLE 3 (a)1-[5,6-Dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone

A solution of5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [5.01g, Reference Example 4(a)] in dry tetrahydrofuran (55 mL), at −78° C.,was treated with a solution of lithium diisopropylamide in a mixture oftetrahydrofuran and heptane (11.9 mL, 2M) over 10 minutes. The mixturewas stirred for 15 minutes then treated dropwise with dimethylacetamide(2.15 mL) over 10 minutes. After stirring at −78° C. for a further 30minutes the reaction mixture was poured into ice (50 g) and then leftuntil all the ice had melted. This mixture was extracted withdichloromethane and the extracts were washed with brine, then withwater, then dried over magnesium sulfate and then evaporated. Theresidual orange oil (5.91 g) was subjected to column chromatography onsilica eluting with a mixture of petroleum ether and ethyl acetate (4:1,v/v) to give1-[5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone(3.93 g) as a yellow crystalline solid.

(b) By proceeding in a similar manner to Reference Example 3(a) abovebut using6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(b)] there was prepared1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone.

(c) By proceeding in a similar manner to Reference Example 3(a) abovebut using5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(c)] there was prepared1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone.

(d) By proceeding in a similar manner to Reference Example 3(a) abovebut using 5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(d)] there was prepared1-[5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone.

(e) By proceeding in a similar manner to Reference Example 3(a) abovebut using 4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(e)] there was prepared1-[4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone.

(f) By proceeding in a similar manner to Reference Example 3(a) abovebut using 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(f)] and dimethylvaleramide [Reference Example 8(a)]there was prepared1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-pentan-1-one.

(g) By proceeding in a similar manner to Reference Example 3(a) abovebut using 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(f)] and dimethylisovalerylamide [Reference Example8(b)] there was prepared3-methyl-1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-one.

(h) By proceeding in a similar manner to Reference Example 3(a) abovebut using 5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole[Reference Example 4(f)] and dimethylpropionamide there was prepared1-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propan-1-one.

REFERENCE EXAMPLE 4 (a)5,6-Dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

A stirred mixture of sodium hydride (1.08 g) in dimethylformamide (80mL) was treated with a solution of 5,6-dimethyl-1H-benzoimidazole (4.95g) in dimethylformamide (50 mL) at room temperature over 10 minutes.After stirring for a further 1 hour the mixture was then treated with2-(trimethylsilanyl)ethoxymethyl) chloride (6.4 mL) over 15 minutes andthen stirring was continued for 18 hours. The reaction mixture wastreated with methanol (15 mL) and water (1 mL) and then evaporated. Theresidue was treated with water (50 mL) and this mixture was thenextracted twice with diethyl ether (80 mL then 50 mL). The combinedextracts were washed three times with water (50 mL), then dried overmagnesium sulfate and then evaporated. The residual brown oil (10.3 g)was purified by Flashmaster using mixtures of ethyl acetate in hexane(20% to 80%) at 40 ml/minute to give5,6-dimethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (7.54g) as an orange oil.

(b) By proceeding in a similar manner to Reference Example 4(a) abovebut using 6-chloro-5-methyl-1H-benzoimidazole [Reference Example 5(a)]there was prepared6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(c) By proceeding in a similar manner to Reference Example 4(a) abovebut using 5-trifluoromethyl-1H-benzoimidazole [Reference Example 5(b)]there was prepared5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(d) By proceeding in a similar manner to Reference Example 4(a) abovebut using 5-fluoro-1H-benzoimidazole [Reference Example 5(c)] there wasprepared 5-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(e) By proceeding in a similar manner to Reference Example 4(a) abovebut using 4-methyl-1H-benzoimidazole [Reference Example 5(d)] there wasprepared 4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(f) By proceeding in a similar manner to Reference Example 4(a) abovebut using 5-methyl-1H-benzoimidazole there was prepared5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole.

(g) By proceeding in a similar manner to Reference Example 4(a) abovebut using 1-(5-methoxy-1H-benzoimidazol-2-yl)-ethanone [ReferenceExample 6(a)] there was prepared1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanone.

(h) By proceeding in a similar manner to Reference Example 4(a) abovebut using (1H-benzoimidazol-2-yl)-1-ethanone and carrying out thereaction in tetrahydrofuran there was prepared1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-ethanoneas a colourless oil.

(i) By proceeding in a similar manner to Reference Example 4(a) abovebut using 1-(5-methoxy-1H-benzoimidazol-2-yl)-propan-1-one [ReferenceExample 6(b)] there was prepared1-[5-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propan-1-one

REFERENCE EXAMPLE 5 (a) 6-chloro-5-methyl-1H-benzoimidazole

A solution of 5-chloro-4-methyl-1,2-phenylenediamine (7.8 g) in amixture of formic acid (35 mL) and hydrochloric acid (300 mL) was heatedat 50° C. for 3 hours then treated with ammonium hydroxide solutionuntil the solution was basic. The reaction mixture was then extractedwith dichloromethane. The extracts were evaporated to give6-chloro-5-methyl-1H-benzoimidazole (7 g).

(b) By proceeding in a similar manner to Reference Example 5(a) abovebut using 4-trifluoromethyl-1,2-phenylenediamine there was prepared5-trifluoromethyl-1H-benzoimidazole.

(c) By proceeding in a similar manner to Reference Example 5(a) abovebut using 4-fluoro-o-phenylenediamine there was prepared5-fluoro-1H-benzoimidazole.

(d) By proceeding in a similar manner to Reference Example 5(a) abovebut using 2,3-diaminotoluene there was prepared4-methyl-1H-benzoimidazole.

REFERENCE EXAMPLE 6 (a) 1-(5-Methoxy-1H-benzoimidazol-2-yl)-ethanone

A stirred mixture of 1-(5-methoxy-1-benzoimidazole)-1-ethanol [5.14 g,Reference Example 7(a)] and manganese dioxide (9 g) in chloroform (80mL) was heated at 60° C. for 18 hours, then cooled to room temperatureand then filtered. The filtrate was evaporated to give1-(5-methoxy-1H-benzoimidazol-2-yl)-ethanone (4.28 g).

(b) 1-(5-Methoxy-1H-benzoimidazol-2-yl)-propan-1-one

By proceeding in a similar manner to Reference Example 6(a) above butusing 1-(5-methoxy-1-benzoimidazole)-1-propanol [Reference Example 7(b)]there was prepared 1-(5-methoxy-1H-benzoimidazol-2-yl)-propan-1-one.

(c) 5-Fluoro-1H-indazole-3-carbaldehyde

By proceeding in a similar manner to Reference Example 6(a) above butusing (5-fluoro-1H-indazol-3-yl)-methanol [Reference Example 25(a)] withacetone as the solvent, a reaction temperature of 55° C. and subjectingthe reaction product to flash column chromatography on silica elutingwith a mixture of 40/60 petrol and ethyl acetate (1:1 v/v) there wasprepared 5-fluoro-1H-indazole-3-carbaldehyde as a light brown solid.LC-MS (METHOD B): R_(T)=2.74 minutes, 165 (M+H)⁺.

(d) 6-Fluoro-1H-indazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 6(a) above butusing (6-fluoro-1H-indazol-3-yl)-methanol [Reference Example 25(b)] withacetone as the solvent, a reaction temperature of 55° C. and subjectingthe reaction product to flash column chromatography on silica elutingwith a mixture of 40/60 petrol and ethyl acetate (1:1 v/v) there wasprepared 6-fluoro-1H-indazole-3-carbaldehyde as a light brown solid.LC-MS (METHOD B): R_(T)=2.74 minutes, 165 (M+H)⁺.

(e) 5-Methyl-1H-indazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 6(a) above butusing (5-methyl-1H-indazol-3-yl)-methanol [Reference Example 25(c)] withdichloromethane as solvent, a reaction temperature of 40° C. andsubjecting the reaction product to flash column chromatography on silicaeluting with a mixture of hexane and ethyl acetate (1:1, v/v) there wasprepared 5-methyl-1H-indazole-3-carbaldehyde as a pale brown solid.LC-MS (METHOD B): R_(T)=2.79 minutes, 161 (M+H)⁺.

(f) 6-Methoxy-1H-indazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 6(a) above butusing (6-methoxy-1H-indazol-3-yl)-methanol [Reference Example 25(e)]with acetone as the solvent, a reaction temperature of 55° C. andsubjecting the reaction product to flash column chromatography on silicaeluting with a mixture of 40/60 petrol and ethyl acetate (1:1 v/v) therewas prepared 6-methoxy-1H-indazole-3-carbaldehyde as a light brownsolid. LC-MS (METHOD B): R_(T)=2.76 minutes, 177 (M+H)⁺.

(g) 4-Phenyl-1H-pyrazole-3-carbaldehyde

By proceeding in a similar manner to Reference Example 6(a) above butusing (4-phenyl-1H-pyrazol-3-yl)-methanol [Reference Example 25(f)] withacetone as the solvent, a reaction temperature of 60° C. for 2 hours,and subjecting the reaction product to flash column chromatography onsilica eluting with a mixture of dichloromethane and methanol (49:1,v/v) there was prepared 4-phenyl-1H-pyrazole-3-carbaldehyde as a whitesolid. LC-MS (METHOD B): R_(T) 2.76 minutes; 213 (M+H)⁺.

(h) 5-Chloro-1H-indazole-3-carbaldehyde

By proceeding in a similar manner to Reference Example 6(a) above butusing (5-chloro-1H-indazol-3-yl)-methanol [Reference Example 25(d)] witha mixture of dichloromethane and tetrahydrofuran as solvent, heating atreflux temperature and subjecting the reaction product to flash columnchromatography on silica eluting with a mixture of hexane and ethylacetate (1:1, v/v) there was prepared5-chloro-1H-indazole-3-carbaldehyde as a pale brown solid. LC-MS (METHODB): R_(T)=2.89 minutes, 181 (M+H)⁺.

(i) 3-Formyl-pyrazole-4-carboxylic acid ethyl ester

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester[Reference Example 41 (a)] there was prepared3-formyl-pyrazole-4-carboxylic acid ethyl ester as a brown solid. LC-MS(METHOD B): R_(T)=2.65 minutes; 169 (M+H)⁺.

(j) 3-Formyl-pyrazole-4-carboxylic acid isopropylamide

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide[Reference Example 41(b)] there was prepared3-formyl-pyrazole-4-carboxylic acid isopropylamide as a waxy orangesolid. LC-MS (METHOD B): R_(T)=2.73 minutes; 182 (M+H)⁺.

(k) 3-Formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester[Reference Example 41(c)] there was prepared3-formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester as a whitesolid. LC-MS (METHOD B): R_(T)=2.80 minutes; 183 (M+H)⁺.

(l) 1H-indazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 6(a) above butusing (1H-indazol-3-yl)-methanol [Reference Example 25(g)] with acetoneas the solvent and carrying out the reaction at reflux temperature for16 hours there was prepared 1H-indazole-3-carbaldehyde as a yellowsolid. LC-MS [METHOD B]; R_(T)=2.63 minutes; 147.26 (M+H)⁺; 145.26(M−H)⁻.

(m) 4-Nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 6(a) above but(i) using [4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol(663 mg, Reference Example 53) and manganese (IV) oxide (2.54 g) withacetone as the solvent, (ii) carrying out the reaction at 65° C. for 2hours and (iii) subjecting the reaction product to flash silicachromatography eluting with a mixture of pentane and ethyl acetate(70:30, v/v), there was prepared4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3 carbaldehyde (191 mg) asa pale yellow oil. LC-MS (Method H): R_(T)=2.19 minutes, 248.24(M+H+Na)⁺.

(n) 3-Formyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide [Reference Example 41 (d)] there was prepared3-formyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide (325 mg)as a yellow oil. LC-MS (METHOD B): R_(T)=2.13 minutes, 198 (M+H)⁺.

(o) 3-Formyl-1H-pyrazole-4-carboxylic acid propylamide

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide[Reference Example 41(e)] there was prepared3-formyl-1H-pyrazole-4-carboxylic acid propylamide (414 mg) as an orangeoil. LC-MS (METHOD B): R_(T)=2.42 minutes, 182 (M+H)⁺.

(p) 3-Formyl-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-amide [Reference Example 41(f)] there wasprepared 3-formyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-amide (400 mg) as a brown oil. LC-MS (METHOD N):R_(T)=2.34 minutes, 224.31 (M+H)⁺.

(q) 3-Formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

By proceeding in a manner similar to Reference Example 6(a) above butusing 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide[Reference Example 41(f)] there was prepared3-formyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (125 mg) as ayellow oil. LC-MS (METHOD H): R_(T)=1.87 minutes, 178.31 (M−H)⁻.

REFERENCE EXAMPLE 7 (a) 1-(5-Methoxy-1H-benzoimidazol-2-yl)-ethanol

A mixture of 4-methoxy-phenylenediamine dihydrochloride (10 g), sodiumL-lactate (10 g) and hydrochloric acid (60 mL, 4M) was heated at 70° C.for 48 hours. The reaction mixture was cooled to room temperature, thentreated with ammonium hydroxide. The resulting precipitate was filteredand dried to give 1-(5-methoxy-1H-benzoimidazol-2-yl)-ethanol (5.14 g).

(b) 1-(5-Methoxy-1-benzoimidazole)-1-propanol

By proceeding in a similar manner to Reference Example 7(a) above butusing 2-hydroxybutyric acid there was prepared1-(5-methoxy-1-benzoimidazole)-1-propanol.

REFERENCE EXAMPLE 8

(a) Dimethylvaleramide

A solution of dimethylamine hydrochloride (6.76 g) and triethylamine (30mL) in dichloromethane (100 mL), under nitrogen and at 0° C. was treateddropwise with valeryl chloride (10 g). After stirring at roomtemperature overnight the reaction mixture was treated with hydrochloricacid (2N) and dichloromethane. The organic phase was separated, driedover magnesium sulfate and then evaporated to give dimethylvaleramide asa clear oil.

(b) By proceeding in a similar manner to Reference Example 8(a) abovebut using isovaleryl chloride there was prepareddimethylisovalerylamide.

REFERENCE EXAMPLE 9 2,3-Diaminopyrazine

Liquid ammonia (50 mL) was introduced into a pressure reaction vesselcontaining a small lump of ice. To this was added copper bronze (1.17g), copper (II) iodide (0.224 g) and 2,3-dichloropyrazine (4 g). Thesealed reaction vessel was heated at 170° C. for 48 hours, then cooledto ambient temperature and then vented. The reaction mixture was treatedwith water (75 mL) and this mixture was extracted four times withdiethyl ether (400 mL). The combined extracts were evaporated to give2,3-diaminopyrazine as a white solid (0.3 g). The aqueous layer wascontinuously extracted with diethyl ether for 18 hours to yield afurther quantity of 2,3-diaminopyrazine (1.24 g). ¹H-NMR [(CD₃)₂SO]: δ5.87 (s, 4H), 7.15 (s, 2H).

REFERENCE EXAMPLE 10 1H-Pyrazole-3-carbaldehyde

(i) Dry dimethylformamide (77.6 mL) was stirred at 80° C. while cyanuricchloride (26.6 g) was added in portions, whilst keeping the reactiontemperature between 80 and 110° C. The reaction mixture was stirred at100° C. for another 30 minutes then cooled and then allowed to stand atroom temperature overnight. The reaction mixture was filtered to givedimethylvinylamine.

(ii) The dimethylvinylamine from (i) was added to dry methanol (260 mL)and the mixture was then treated with pyruvic aldehyde dimethylacetal(51 mL), followed by a solution of sodium methoxide in methanol (30%, 81mL), then stirred for 2 hours at ambient temperature, then heated atreflux temperature for another hour, then cooled and then filtered. Thefiltrate was evaporated to give 1,1-dimethoxy-but-3-en-2-one as a brownoil (96.8 g).

(iii) A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300μL) was treated dropwise with hydrazine hydrate (21 mL). After standingat room temperature overnight the reaction mixture was treated withsodium chloride (108 g) and the mixture was then extracted withmethyl-t-butylether (200 mL then 100 mL). The combined extracts weredried with magnesium sulfate and then evaporated to give1H-pyrazol-3-carbaldehyde dimethyl acetal as a light brown oil (18.47g).

(iv) A solution of 1H-pyrazol-3-carbaldehyde dimethyl acetal in water(85 mL) was treated with glacial acetic acid (3.7 mL). After two daysthe mixture was filtered to give 1H-pyrazole-3-carbaldehyde (1.3 g) as alight brown solid.

REFERENCE EXAMPLE 112-(5-Ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

Sodium hydride (0.1 g) was added to ethanol (5 mL) and the mixture wasstirred for ten minutes, then treated with3,3-bis-methanesulfanyl-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[0.5 g, Reference Example 2(p)] and then heated at reflux temperaturefor six hours. The reaction mixture was cooled, then treated withhydrazine hydrate (1.27 mmol) and then heated at reflux temperature forfour hours. The mixture was then evaporated and the residue wastriturated with water and filtered. The solid was subjected tochromatography on silica gel eluting with ethyl acetate to give2-(5-ethoxy-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazoleas a yellow oil.

REFERENCE EXAMPLE 122-(5-Methylsulfanyl-isoxazol-3-yl)-1-(trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole

Hydroxylamine hydrochloride (168 mg) was added to a solution of sodiummethoxide in methanol [prepared by the addition of sodium hydride (122mg) to methanol (5 mL)]. The mixture was stirred for ten minutes, thentreated with3,3-bis-methanesulfanyl-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propenone[500 mg, Reference Example 2(p)], then heated at reflux for six hours,then cooled and then evaporated. The residue was taken up in water andthe aqueous mixture was extracted with ethyl acetate. The extracts weredried and evaporated. The residue was subjected to chromatography onsilica eluting with methylene chloride to give2-(5-methylsulfanyl-isoxazol-3-yl)-1-(trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole(0.16 g) as a colourless oil.

REFERENCE EXAMPLE 131-[6-Chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3-methylsulfanyl-3-morpholin-1-yl-propenone

A solution of1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3,3-bis-methanesulfanyl-propenone[800 mg, Reference Example 2(q)] in morpholine (3 m]L) was heated at 95°C. for 2 hours and then evaporated to give1-[6-chloro-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-3-methylsulfanyl-3-morpholin-1-yl-propenone.

REFERENCE EXAMPLE 14 2-Chloromethyl-thiophene

To a three-necked flask fitted with stirrer bar, pressure equalizingdropping funnel and inlet/outlet adapter was added thiophene (10 mL) andaqueous hydrochloric acid (5.5 mL). Hydrogen chloride gas [generated bydropping sulfuric acid (30 mL) onto dry sodium chloride (50 g)] wasbubbled through the reaction mixture with vigorous stirring at 0° C.This mixture was then treated dropwise with formaldehyde solution (37%,12.5 mL) and stirring was continued for 45 minutes. The phases wereseparated and the aqueous phase was extracted three times with diethylether (10 mL). The organic phases were then washed twice with water (10mL), then twice with saturated sodium hydrogen carbonate (10 mL), thendried over magnesium sulfate and then evaporated. The residue wasdistilled at 20 mmHg using a heat gun to give 2-chloromethyl-thiophenewhich was used immediately without further purification.

REFERENCE EXAMPLE 15Bis(methylthio)-3,3-(benzoimidazol-2-yl)-1-prop-2-en-2-one

A mixture of sodium hydride (19.2 g) and toluene (400 mL), at 80° C.,was treated portionwise with tertiary-butanol (30.8 g). After 2 hoursthe reaction mixture was cooled to room temperature and treated dropwisewith a mixture of dimethylformamide (40 mL), carbon disulfide (12 mL)and 2-acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole (51 g, ReferenceExample 16) over 90 minutes. After addition the red reaction mixture wasstirred at 80° C. for 30 minutes, then cooled to room temperature andthen treated with methyl iodide (50 mL). This mixture was stirred at 80°C. for 30 minutes when a precipitate started to form. The reactionmixture was cooled to room temperature and then filtered. The filtratewas concentrated to give a viscous red oil, which was dissolved inmethanol (300 mL). This solution was treated with p-toluenesulfonic acid(2 g) and water (4 mL), then heated at reflux temperature for 13 hoursand then cooled in an ice-bath. The resulting solid was filtered andthen washed with isopropyl ether to givebis(methylthio)-3,3-(benzoimidazol-2-yl)-1-prop-2-en-2-one (11.2 g),m.p. 224° C.

REFERENCE EXAMPLE 16 2-Acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole

Dihydropyran (20.5 mL) as added dropwise to a solution of2-acetylbenzoimidazole (32 g) and p-toluenesulfonic acid (2 g) indichloromethane (280 mL) at reflux. The reaction mixture was stirred atthis temperature for 24 hours, then cooled and the insoluble materialswere filtered off. The filtrate was concentrated to give2-acetyl-1-(tetrahydropyran-2-yl)-benzoimidazole as an amber oil (51.8g). TLC: (dichloromethane:methanol, 97:3) R_(F)=0.80.

REFERENCE EXAMPLE 17 (a) 4,5,6,7-Tetrahydro-1H-indazole-3-carboxylicacid

A solution of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethylester [0.606 g, Reference Example 18(a)] in methanol (50 ml) was treatedwith sodium hydroxide (0.500 g). The mixture was refluxed for 16 hours,then cooled and then evaporated. The residual white solid was treatedwith hydrochloric acid (30 ml, 2N) and the resulting solution wasextracted three times with ethyl acetate (50 ml). The combined organicextracts were dried over sodium sulfate and then evaporated to yield4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.424 g) as a whitesolid. LC-MS (METHOD B): R_(T)=2.44 minutes; 167 (M+H)⁺.

(b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid

By proceeding to a manner similar to Example 17(a) above but using5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester [Reference Example18(b)], there was prepared 5-isopropyl-1H-pyrazole-3-carboxylic acid asa white solid (0.973 g) which was used without further purification.

LC-MS (METHOD B): R_(T)=2.43 minutes; 155 (M+H)⁺.

(c) 5-Ethyl-1H-pyrazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 17(a) above, butusing 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester [ReferenceExample 18(c)], there was prepared 5-ethyl-1H-pyrazole-3-carboxylic acidas a white solid. LC-MS (METHOD B): R_(T)=2.34 minutes; 141 (M+H)⁺.

(d) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid

By proceeding in a manner similar to Reference Example 17(a) above, butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester[Reference Example 42], there was prepared3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid as a white solidwhich was used without further purification. LC-MS (METHOD B):R_(T)=2.75 minutes; 199 (M+H)⁺.

(e) 1,4,6,7-Tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 17(a) above butusing 1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid ethylester [Reference Example 18(e)] there was prepared1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid (261 mg) as awhite solid. LC-MS (METHOD B): R_(T) 1.98 minutes, 169 (M+H)⁺.

(f) 1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 17(a) above butusing 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethylester [Reference Example 18(f)] there was prepared1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid (0.641 g) as awhite solid. LC-MS (METHOD B): R_(T)=2.13 minutes, 153.22 (M+H)⁺.

REFERENCE EXAMPLE 18 (a) 4,5,6,7-Tetrahydro-1H-indazole-3-carboxylicacid ethyl ester

A solution of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester [7.5 g,Reference Example 19(a)] in acetic acid (150 ml) was treated dropwisewith hydrazine monohydrate (1.65 ml). The mixture was refluxed for 8hours, then cooled and then evaporated. The residue was partitionedbetween ethyl acetate (200 ml) and saturated sodium bicarbonate solution(200 ml) and the organic layer was dried over sodium sulfate and thenevaporated. The residual orange oil was subjected to flash columnchromatography on silica eluting with a mixture of ethyl acetate andhexane (1:1, v/v) to give 4,5,6,7-tetrahydro-1H-indazole-3-carboxylicacid ethyl ester (606 mg) as an orange oil which solidified on standing.LC-MS (METHOD B): R_(T)=2.79 minutes; 195 (M+H)⁺.

(b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

By proceeding to a manner similar to Reference Example 18(a) above butusing 5-methyl-2,4-dioxo-hexanoic acid ethyl ester [2.00 g, ReferenceExample 19(b)] there was prepared 5-isopropyl-1H-pyrazole-3-carboxylicacid ethyl ester as a light yellow oil which was used without furtherpurification. LC-MS (METHOD B): R_(T)=2.79 minutes; 183 (M+H)⁺.

(c) 5-Ethyl-1H-pyrazole-3-carboxylic acid ethyl ester

By proceeding in a manner similar to Reference Example 18(a) above, butusing 2,4-dioxo-hexanoic acid ethyl ester [Reference Example 19(c)], andsubjecting the reaction product, an orange oil, to flash chromatographyon silica eluting with a mixture of ethyl acetate and hexane (8:1, v/v),there was prepared 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester asa yellow oil. LC-MS (METHOD B): R_(T)=2.64 minutes; 169 (M+H)⁺.

(d) 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester 3-ethyl ester

By proceeding in a manner similar to Reference Example 18(a) above, butusing 3-ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester[Reference Example 19(d)], there was prepared1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester 3-ethyl ester as a yellow oil. LC-MS (METHOD B):R_(T)=2.73 minutes; 296 (M+H)⁺.

(e) 1,4,6,7-Tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid ethylester

By proceeding in a manner similar to Reference Example 18(a) above butusing tetrahydro-4H-pyran-4-one there was prepared1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid ethyl ester(385 mg) as a white solid. LC-MS (METHOD B): R_(T)=2.43 minutes, 197(M+H)⁺.

(f) 1,4,5,6-Tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester

By proceeding in a manner similar to Reference Example 18(a) above butusing oxo-(2-oxo-cyclopentyl)-acetic acid ethyl ester [Reference Example19(e)] there was prepared1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester(2.06 g) as a yellow solid. LC-MS (METHOD B): R_(T)=2.56 minutes, 185(M+H)⁺.

REFERENCE EXAMPLE 19 (a) Oxo-(2-oxo-cyclohexyl-acetic acid ethyl ester

A solution of sodium (1.75 g) in ethanol (100 ml) was treated with amixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). Themixture was heated to 60° C. for 5 hours then cooled and then evaporatedto yield oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester as a brown foam(16.635 g). LC-MS (METHOD B): R_(T) 3.10 minutes; 197 (M−H)⁻.

(b) 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester

By proceeding to a manner similar to Example 19(a) above but using3-methyl-2-butanone there was prepared 5-methyl-2,4-dioxo-hexanoic acidethyl ester as a white solid. LC-MS (METHOD B): R_(T)=3.47 minutes; 187(M+H)⁺.

(c) 2,4-Dioxo-hexanoic acid ethyl ester

By proceeding in a manner similar to Reference Example 19(a) above, butusing 2-butanone, there was prepared 2,4-dioxo-hexanoic acid ethyl esteras a brown oil which was used without further purification. LC-MS(METHOD B): R_(T)=3.28 minutes; 173 (M+H)⁺.

(d) 3-Ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 19(a) above, butusing N-Boc piperidone, there was prepared3-ethoxyoxalyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester as abrown oil which was used without further purification. LC-MS (METHOD B):R_(T)=3.43 minutes; 244 (M−tBu)⁺.

(e) Oxo-(2-oxo-cyclopentyl)-acetic acid ethyl ester

By proceeding in a manner similar to Reference Example 19(a) above butusing cyclopentanone there was prepared oxo-(2-oxo-cyclopentyl)-aceticacid ethyl ester (9.99 g) as a yellow solid. LC-MS (METHOD B):R_(T)=3.12 minutes, 185 (M+H)⁺.

REFERENCE EXAMPLE 20 (a) 3-Formyl-5-methoxy-indazole-1-carboxylic acidtert-butyl ester

A solution of5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester [282 mg, Reference Example 21(a)] in tetrahydrofuran (4ml) and water (1.5 ml) was treated with a solution of osmium tetroxidein water (54 μL, 4 wt %) and sodium periodate (400 mg). The reactionmixture was stirred at ambient temperature for 16 hours and thenfiltered. The filtrate was evaporated and the residue was partitionedbetween ethyl acetate and water. The organic layer was dried overmagnesium sulfate and then evaporated. The residue was subjected toflash column chromatography on silica eluting with a mixture of ethylacetate and petrol (1:9, v/v) to yield3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester (162 mg)as a white solid. LC-MS (METHOD B): R_(T)=2.97 minutes; 277 (M+H)⁺.

(b) 4-Fluoro-1H-indazole-3-carbaldehyde

By proceeding in a manner similar to Reference Example 20(a) but using4-fluoro-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester [Reference Example 21(b)] there was prepared4-fluoro-1H-indazole-3-carbaldehyde as a light brown solid. LC-MS(METHOD B): R_(T)=2.63 minutes; 165 (M+H)⁺.

(c) 4-Chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 20(a) but using4-chloro-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester [Reference Example 21(c)] there was prepared4-chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester (0.217 g)as a brown oil. LC-MS (METHOD B): R_(T)=3.49 minutes; 283 (M+H)⁺.

(d) 5-Ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 20(a) but using5-ethoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester [Reference Example 21(d)] there was prepared5-ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester as a brownoil. TLC(ethyl acetate:hexane, 1:9, v/v): R_(F)=0.25. ¹HNMR (400 MHz,CDCl₃): δ 1.38 (3H, t), 1.67 (9H, s), 4.05 (2H, q), 7.12 (1H, d), 7.60(1H, s), 7.98 (1H, d), 10.20 (1H, s).

REFERENCE EXAMPLE 21 (a)5-Methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester

A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butylester [0.500 g, Reference Example 22(a)] in dioxane (15 ml) and under anatmosphere of nitrogen was treated with triethylamine (1.86 ml) followedby methyl acrylate (1.20 ml), triphenylphosphine (0.105 g), andpalladium (II) acetate (60 mg). The resulting mixture was heated at 50°C. for 16 hours, then cooled to ambient temperature and then evaporated.The residue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, then dried over magnesium sulfate and thenevaporated. The residue was subjected to flash column chromatography onsilica eluting with a mixture of ethyl acetate and 40/60 petrol (1:9,v/v) to yield5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester (282 mg). LC-MS (METHOD B): R_(T)=3.33 minutes; 333(M+H)⁺.

(b) By proceeding in a manner similar to Reference Example 21(a) butusing 4-fluoro-3-iodo-indazole-1-carboxylic acid tert-butyl ester[Reference Example 22(b)] there was prepared4-fluoro-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester as a light brown solid.

LC-MS (METHOD B): R_(T)=3.39 minutes; 321 (M+H)⁺.

(c) By proceeding in a manner similar to Reference Example 21 (a) butusing 4-chloro-3-iodo-indazole-1-carboxylic acid tert-butyl ester[Reference Example 22(c)] there was prepared4-chloro-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester as a brown solid.

LC-MS (METHOD B): R_(T)=3.48 minutes; 339 (M+H)⁺.

(d) By proceeding in a manner similar to Reference Example 21(a) butusing 5-ethoxy-3-iodo-indazole-1-carboxylic acid tert-butyl ester[Reference Example 22(d)] there was prepared5-ethoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acidtert-butyl ester as an off-white solid. LC-MS (METHOD B): R_(T)=3.41minutes; 347 (M+H)⁺.

REFERENCE EXAMPLE 22 (a) 3-Iodo-5-methoxy-indazole-1-carboxylic acidtert-butyl ester

A solution of 3-iodo-5-methoxy-1H-indazole [1.48 g, Reference Example23(a)] in acetonitrile (6 ml) was treated with triethylamine (0.98 ml)and N,N-dimethylaminopyridine (0.132 g). The mixture was cooled to 0° C.then treated with a solution of di-tert-butyl dicarbonate (1.41 g) inacetonitrile (6 ml). After stirring for 1 hour at ambient temperaturethe reaction mixture was evaporated and the residue was partitionedbetween ethyl acetate and water. The pH was adjusted to 2 and theorganic layer was dried over magnesium sulfate and then evaporated. Theresidual orange oil was subjected to flash column chromatography onsilica eluting with a mixture of ethyl acetate and petrol (1:4, v/v) toyield 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butyl ester (1.72g) as a yellow solid.

LC-MS (METHOD B): R_(T)=3.45 minutes; 375 (M+H)⁺.

(b) 4-Fluoro-3-iodo-indazole-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 22(a) above butusing 4-fluoro-3-iodo-1H-indazole [Reference Example 23(b)] there wasprepared 4-fluoro-3-iodo-indazole-1-carboxylic acid tert-butyl ester asa light brown solid. LC-MS (METHOD B): R_(T)=3.48 minutes; 363 (M+H)⁺.

(c) 4-Chloro-3-iodo-indazole-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 22(a) above butusing 4-chloro-3-iodo-1H-indazole [Reference Example 23(c)] there wasprepared 4-chloro-3-iodo-indazole-1-carboxylic acid tert-butyl ester asa brown solid. LC-MS (METHOD B): R_(T)=3.39 minutes; 381 (M+H)⁺.

(d) 5-Ethoxy-3-iodo-indazole-1-carboxylic acid tert-butyl ester

By proceeding in a manner similar to Reference Example 22(a) above butusing 5-ethoxy-3-iodo-1H-indazole [Reference Example 23(d)] there wasprepared 5-ethoxy-3-iodo-indazole-1-carboxylic acid tert-butyl ester asan off-white solid. LC-MS (METHOD B): R_(T)=3.49 minutes; 389 (M+H)⁺.

REFERENCE EXAMPLE 23 (a) 3-Iodo-5-methoxy-1H-indazole

A solution of 5-methoxy-1H-indazole [0.815 g, Reference Example 24(a)]in dimethyl formamide (8 ml) was treated with iodine (2.80 g) andpotassium hydroxide (1.16 g). The mixture was stirred at ambienttemperature for 1 hour then poured into 10% aqueous sodium bisulfitesolution (200 ml) and then extracted three times with ethyl acetate. Thecombined organic extracts were washed with water, then with brine, thendried over magnesium sulfate and then evaporated to yield3-iodo-5-methoxy-1H-indazole (1.48 g) as a yellow solid. LC-MS (METHODB): R_(T)=2.96 minutes; 275 (M+H)⁺.

(b) 4-Fluoro-3-iodo-1H-indazole

By proceeding in a manner similar to Reference Example 23(a) above butusing 4-fluoro-1H-indazole [Reference Example 24(b)] there was prepared4-fluoro-3-iodo-1H-indazole as a red solid.

LC-MS (METHOD B): R_(T)=3.06 minutes; 281 (M+H)⁺.

(c) 4-Chloro-3-iodo-1H-indazole

By proceeding in a manner similar to Reference Example 23(a) above butusing 4-chloro-1H-indazole [Reference Example 24(c)] there was prepared4-chloro-3-iodo-1H-indazole as a light brown solid. LC-MS (METHOD B):R_(T)=2.97 minutes; 263 (M+H)⁺.

(d) 5-Ethoxy-3-iodo-1H-indazole

By proceeding in a manner similar to Reference Example 23(a) above butusing 5-ethoxy-1H-indazole [Reference Example 37] there was prepared5-ethoxy-3-iodo-1H-indazole as a light brown solid. LC-MS (METHOD B):R_(T)=2.97 minutes; 263 (M+H)⁺.

REFERENCE EXAMPLE 24 (a) 5-Methoxy-1H-indazole

A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10ml) was treated with triethylamine (3.27 ml). The mixture was cooled to0° C. then treated with acetic anhydride (2.38 ml), then stirred atambient temperature for 1 hour, then cooled to 0° C. when a pink solidprecipitated. This solid was filtered, then washed with colddichloromethane and then dissolved in acetic acid (55 ml) andconcentrated hydrochloric acid (20 ml). This solution was cooled to −5°C., then treated with a solution of sodium nitrite (2.68 g) in water (20ml), then stirred at that temperature for 1 hour and then treated withwater (100 ml). This mixture was stirred vigorously at 0° C. for 10minutes after which a yellow solid precipitated. This solid wasfiltered, then washed with water and then dissolved in toluene (13 ml).This solution was heated to 80° C. for 1.5 hours, then cooled and thenwashed with aqueous 1N sodium carbonate solution. The organic phase wasextracted three times with aqueous 2N hydrochloric acid and the acidextracts chilled and then made alkaline by addition of aqueous 5N sodiumhydroxide solution. The aqueous layers were extracted three times withethyl acetate and the combined organic layers were dried over magnesiumsulfate and then evaporated to yield 5-methoxy-1H-indazole (0.410 g) asa yellow solid. LC-MS (METHOD B): R_(T)=1.32 minutes; 149 (M+H)⁺.

(b) 4-Fluoro-1H-indazole

To tetrafluoroboric acid (8.2 ml, 48 wt % in water) was added3-fluoro-2-methylaniline (2.27 ml). The mixture was cooled to 0° C. whena precipitate formed which was redissolved by the addition of water (8ml). A solution of sodium nitrite (1.38 g) in water (2.7 ml) was thenadded dropwise and the mixture was then allowed to warm to ambienttemperature and then stirred for a further 1 hour. The precipitatedsolid was filtered, then washed with diethyl ether, and then dried undersuction for 30 minutes. The resulting tetrafluoroborate salt was addedto a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264 g)in chloroform (45 ml). After stirring for 3 hours at ambient temperaturethe bright orange mixture was filtered and the insoluble material waswashed with dichloromethane, then subjected to flash columnchromatography on silica eluting with a mixture of 40/60 petrol andethyl acetate (3:1 v/v) to give 4-fluoro-1H-indazole (0.675 g) as anoff-white solid. LC-MS (METHOD B): R_(T)=2.70 minutes; 137 (M+H)⁺.

(c) 4-Chloro-1H-indazole

By proceeding to a manner similar to Reference Example 24(a) above butusing 3-chloro-2-methylaniline, there was prepared 4-chloro-1H-indazoleas a red solid (0.807 g) which was used without further purification.LC-MS (METHOD B): R_(T)=2.90 minutes; 155 (M+H)⁺.

REFERENCE EXAMPLE 25 (a) (5-fluoro-1H-indazol-3-yl)-methanol

A solution of 5-fluoro-1H-indazole-3-carboxylic acid [0.680 g, ReferenceExample 26(a)] in anhydrous tetrahydrofuran (15 ml), at 0° C., wastreated portionwise with lithium aluminium hydride (0.716 g), thenstirred for 2 hours at ambient temperature and then treated withsaturated aqueous sodium sulfate. The reaction mixture was acidified byaddition of hydrochloric acid (1N) and then extracted three times withethyl acetate (30 ml). The combined organic extracts were dried overmagnesium sulfate and then evaporated. The residual dark brown oil wassubjected to flash column chromatography on silica eluting with amixture of 40/60 petrol and ethyl acetate (1:1 to 1:3 v/v) to yield(5-fluoro-1H-indazol-3-yl)-methanol (0.144 g) as a brown solid. LC-MS(METHOD B): R_(T)=2.40 minutes; 167 (M+H)⁺.

(b) (6-Fluoro-1H-indazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing 6-fluoro-1H-indazole-3-carboxylic acid [Reference Example 26(b)]there was prepared (6-fluoro-1H-indazol-3-yl)-methanol (0.265 g) as adark grey solid. LC-MS (METHOD B): R_(T)=2.40 minutes, 165 (M−H).

(c) (5-Methyl-1H-indazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing 5-methyl-1H-indazole-3-carboxylic acid [Reference Example 26(c)]there was prepared (5-methyl-1H-indazol-3-yl)-methanol (0.511 g) as abrown oil. LC-MS (METHOD B): R_(T)=2.45 minutes; 163 (M+H)⁺.

(d) (5-Chloro-1H-indazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing 5-chloro-1H-indazole-3-carboxylic acid [Reference Example 26(d)]there was prepared (5-chloro-1H-indazol-3-yl)-methanol as a dark brownoil which solidified on standing. LC-MS (METHOD B): R_(T)=2.51 minutes;185 (M+H)⁺.

(e) (6-Methoxy-1H-indazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing 6-methoxy-1H-indazole-3-carboxylic acid [Reference Example 26(e)]there was prepared (6-methoxy-1H-indazol-3-yl)-methanol (0.265 g) as abrown solid. LC-MS (METHOD B): R_(T)=2.37 minutes; 179 (M+H)⁺.

(f) (4-Phenyl-1H-pyrazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing 4-phenyl-1H-pyrazole-3-carboxylic acid [Reference Example 47] andsubjecting the reaction product to flash column chromatography on silicaeluting with a mixture of dichloromethane and methanol (9:1, v/v) therewas prepared (4-phenyl-1H-pyrazol-3-yl)-methanol. LC-MS (METHOD B):R_(T)=2.51 minutes; 175 (M+H)⁺.

(g) (1H-indazol-3-yl)-methanol

By proceeding in a manner similar to Reference Example 25(a) above butusing indazole-3-carboxylic acid and subjecting the reaction product tocolumn chromatography on silica eluting with a mixture of a mixture ofn-hexane and ethyl acetate (1:1) to ethyl acetate there was prepared(1H-indazol-3-yl-methanol as a pale yellow solid. LC-MS (METHOD B):R_(T)=3.17 minutes; 149.21([M+H]⁺.

REFERENCE EXAMPLE 26 (a) 5-Fluoro-1H-indazole-3-carboxylic acid

A solution of 5-fluoroisatin (2 g) and sodium hydroxide (0.509 g) inwater (20 ml) was heated to 50° C. for 30 minutes, then cooled and thentreated with sodium nitrite (0.836 g). This mixture was added over 10minutes to a solution of concentrated sulfuric acid (2.26 g) in water(200 ml), at 0° C., whilst maintaining the temperature below 5° C. Aftera further 15 minutes a solution of tin (II) chloride (5.51 g) inconcentrated hydrochloric acid (10.5 ml) was added and the resultingmixture maintained at 5° C. for a further 30 minutes. The mixture wasthen stirred for a further 1 hour whilst warming to ambient temperaturethen filtered. The light brown paste was dissolved in ethyl acetate andthe solution was dried over magnesium sulfate and then evaporated toyield 5-fluoro-1H-indazole-3-carboxylic acid (0.863 g) as a light brownsolid which was used without further purification.

LC-MS (METHOD B): R_(T)=2.51 minutes; 181 (M+H)⁺.

(b) 6-Fluoro-1H-indazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 26(a) above butusing 6-fluoro-1H-indole-2,3-dione [Reference Example 27(a)] there wasprepared 6-fluoro-1H-indazole-3-carboxylic acid (1.962 g) as a lightbrown solid. LC-MS (METHOD B): R_(T)=2.50 minutes; 181 (M+H)⁺.

(c) 5-Methyl-1H-indazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 26(a) above butusing 5-methyl isatin there was prepared5-methyl-1H-indazole-3-carboxylic acid as a light brown solid. LC-MS(METHOD B): R_(T)=2.53 minutes; 177 (M+H)⁺.

(d) 5-Chloro-1H-indazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 26(a) above butusing 5-chloro isatin there was prepared5-chloro-1H-indazole-3-carboxylic acid as a light brown solid. LC-MS(METHOD B): R_(T)=2.58 minutes; 171 (M+H)⁺.

(e) 6-Methoxy-1H-indazole-3-carboxylic acid

By proceeding in a manner similar to Reference Example 26(a) above butusing 6-methoxy-1H-indole-2,3-dione [2.50 g, Reference Example 27(b)]there was prepared 6-methoxy-1H-indazole-3-carboxylic acid as a lightbrown solid. LC-MS (METHOD B): R_(T)=2.45 minutes; 193 (M+H)⁺.

REFERENCE EXAMPLE 27 (a) 6-Fluoro-1H-indole-2,3-dione

To vigorously stirring polyphosphoric acid (10 g) at 75° C. was addedN-(3-fluoro-phenyl)-2-hydroxyimino-acetamide [10.304 g, ReferenceExample 28(a)] portionwise over 30 minutes. The resulting mixture wasstirred at 80° C. for 15 minutes, then poured into ice, then left tostand for 16 hours and then filtered to give a brown paste. The filtratewas extracted four times with ethyl acetate. The combined organicfractions were dried over magnesium sulfate and then evaporated. Theresidue and the brown paste from the filtration above were combined andtreated with aqueous sodium hydroxide (1N). The mixture was filtered andthe filtrate was acidified by addition of aqueous hydrochloric acid(2N). The resulting brown solid was filtered and then treated withaqueous sodium hydroxide (1N). This mixture was filtered and thefiltrate was acidified by addition of aqueous hydrochloric acid (2N) andthen filtered. The combined acidic aqueous filtrates were extracted fourtimes with ethyl acetate, then dried over magnesium sulfate, and thenevaporated to give 6-fluoro-1H-indole-2,3-dione (1.861 g) as a paleorange solid. LC-MS (METHOD B): R_(T)=2.49 minutes; 166 (M+H)⁺.

(b) 6-Methoxy-1H-indole-2,3-dione

By proceeding in a manner similar to Reference Example 27(a) above butusing 2-hydroxyimino-N-(3-methoxy-phenyl)-acetamide [7.20 g, ReferenceExample 28(b)] there was prepared 6-methoxy-1H-indole-2,3-dione as abrown solid. LC-MS (METHOD B): R_(T)=2.49 minutes; 178 (M+H)⁺.

REFERENCE EXAMPLE 28 (a) N-(3-Fluoro-phenyl)-2-hydroxyimino-acetamide

A mixture of chloral hydrate (0.819 g) in water (25 ml) was treated withsodium sulfate (5.10 g), 3-fluoroaniline (0.43 ml), concentratedhydrochloric acid (0.3 ml), and hydroxylamine hydrochloride (0.938 g).The mixture was warmed to 80° C. for 2 hours then allowed to cool andthen filtered. The solid was washed with water and then dried in air for16 hours to afford N-(3-fluoro-phenyl)-2-hydroxyimino-acetamide (0.756g) as a buff solid. LC-MS (METHOD B): R_(T)=2.51 minutes; 181 (M+H)⁺.

(b) 2-Hydroxyimino-N-(3-methoxy-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 28(a) above butusing m-anisidine (0.5 ml) there was prepared2-hydroxyimino-N-(3-methoxy-phenyl)-acetamide as a brown solid. LC-MS(METHOD B): R_(T)=2.44 minutes; 195 (M+H)⁺.

REFERENCE EXAMPLE 29 (a) 4-Ethyl-phenylene diamine

A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Reference Example30(a)] and tin chloride (2.75 g) in ethanol (5 ml) was heated in a SmithCreator microwave at 140° C. for 10 minutes. The reaction mixture wasbasified to pH 8 by addition of saturated sodium hydrogen carbonatesolution and then extracted with ethyl acetate. The organic extractswere dried over magnesium sulfate and then evaporated to give4-ethyl-phenylene diamine (140 mg) as a pale orange solid, which wasused without future purification. MS: 137.2 (M+H)⁺. HPLC (METHOD H):R_(T)=2.91 minutes.

(b) 4-Methoxy-5-methyl-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 29(a) above butusing 4-methoxy-5-methyl-2-nitro-phenylamine [582 mg, Reference Example31(i)] there was prepared 4-methoxy-5-methyl-benzene-1,2-diamine (454mg) as a light brown solid. LC-MS (Method K): R_(T)=2.39 minutes, 153.20(M+H)⁺.

(c) 4-(2-Morpholin-4-yl-ethoxy)-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 29(a) above butusing 4-[2-(3,4-dinitro-phenoxy)-ethyl]-morpholine [Reference Example67] there was prepared 4-(2-morpholin-4-yl-ethoxy)-benzene-1,2-diamine(170 mg) as a pale brown oil. LC-MS (METHOD N): R_(T)=2.2 minutes,238.21 (M+H)⁺.

REFERENCE EXAMPLE 30 (a) 4-Ethyl-5-methyl-phenylene diamine

A stirred solution of 4-ethyl-5-methyl-2-nitro-aniline [484 mg,Reference Example 31 (b)] in methanol (20 ml) was treated with tinchloride (5.09 g), then heated at reflux for 16 hours and then cooled toambient temperature. The pH of the reaction mixture was adjusted to pH 8by addition of aqueous sodium bicarbonate and then this mixture wasextracted with ethyl acetate. The organic extracts were dried overmagnesium sulfate and then evaporated to give 4-ethyl-5-methyl-phenylenediamine (374 mg) as an off-white solid. LC-MS (METHOD B): R_(T)=1.80minutes; 151.25 (M+H)⁺.

(b) 4-Isopropyl-5-methyl-phenylene diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-isopropyl-5-methyl-2-nitro-aniline [Reference Example 31(c)]there was prepared 4-isopropyl-5-methyl-phenylene diamine as a lightbrown solid. LC-MS (Method C): R_(T)=3.30 minutes; 165.16 (M+H)⁺.

(c) 4-Bromo-5-methyl-phenylene diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-bromo-5-methyl-2-nitro-aniline [Reference Example 31 (d)] therewas prepared 4-bromo-5-methyl-phenylene diamine as an off-white solid.LC-MS (METHOD B): R_(T)=2.63 minutes; 203.22 (M+H)⁺.

(d) 4-n-propyl-phenylene diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-n-propyl-2-nitro-aniline [Reference Example 31 (e)] there wasprepared 4-n-propyl-phenylene diamine as an off-white solid. LC-MS(METHOD B): R_(T)=2.07 minutes, 151.30 (M+H)⁺.

(e) 4-Bromo-phenylene diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-bromo-2-nitro-aniline there was prepared 4-bromo-phenylenediamine as a yellow solid. LC-MS (METHOD B): R_(T)=1.77 minutes; 187.22(M+H)⁺.

(f) 3′,4′-diaminobophenyl-3-carbonitrile

By proceeding in a manner similar to Reference Example 30(a) above butusing 4′-amino-3′-nitro-biphenyl-3-carbonitrile [Reference Example34(a)] there was prepared 3′,4′-diaminobophenyl-3-carbonitrile as anoff-white solid. LC-MS (METHOD B): R_(T)=2.72 minutes; 210.3 (M+H)⁺.

(g) 4-(pyridine-3-yl)benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 2-nitro-4-pyridine-3-yl-phenylamine [Reference Example 34(b)]there was prepared 4-(pyridine-3-yl)benzene-1,2-diamine as an off-whitesolid. LC-MS (METHOD B): R_(T)=0.37 minutes; 186.3 (M+H)⁺.

(h) 6-methylbiphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 2-methyl-5-nitro-biphenyl-4-ylamine [Reference Example 34(c)]there was prepared 6-methylbiphenyl-3,4-diamine as an off-white solid.LC-MS (METHOD B): R_(T)=2.36 minutes; 199.25 (M+H)⁺.

(i) biphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 3-nitrobiphenyl-4-ylamine [Reference Example 34(d)] there wasprepared biphenyl-3,4-diamine as a yellow solid. LC-MS (METHOD B):R_(T)=2.25 minutes; 185.3 (M+H)⁺.

(j) 2′-fluorobiphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 2′-fluoro-3-nitro-biphenyl-4-ylamine [Reference Example 34(e)]there was prepared 2′-fluorobiphenyl-3,4-diamine as a white solid. LC-MS(METHOD B): R_(T)=2.73 minutes; 203.31 (M+H)⁺.

(k) 4-benzo[1,3]dioxol-5-ylbenzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-benzo[1,3]dioxo-5-yl-2-nitrophenylamine [Reference Example34(f)] there was prepared 4-benzo[1,3]dioxol-5-ylbenzene-1,2-diamine asa white solid. LC-MS (METHOD B): R_(T)=2.66 minutes; 229.3 (M+H)⁺.

(l) 2′-methoxybiphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 2′-methoxy-3-nitro-biphenyl-4-ylamine [Reference Example 34(g)]there was prepared 2′-methoxybiphenyl-3,4-diamine as a white solid.LC-MS (METHOD B): R_(T)=2.74 minutes; 215.33 (M+H)⁺.

(m) 4′-chlorobiphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4′-chloro-3-nitro-biphenyl-4-yl-amine [Reference Example 34(h)]there was prepared 4′-chlorobiphenyl-3,4-diamine diamine as a whitesolid. LC-MS (METHOD B): R_(T)=2.85 minutes; 219.3 (M+H)⁺.

(n) 4′-methylbiphenyl-3,4-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4′-methyl-3-nitro-biphenyl-4-yl-amine [Reference Example 34(i)]there was prepared 4′-methylbiphenyl-3,4-diamine as a white solid. LC-MS(METHOD B): R_(T)=2.39 minutes, 199.25 (M+H)⁺.

(o) 4-benzyloxybenzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-benzyloxy-1,2-dinitrobenzene [Reference Example 35(a)] there wasprepared 4-benzyloxybenzene-1,2-diamine as a white solid. LC-MS (METHODB): R_(T)=2.34 minutes, 215.33 (M+H)⁺.

(p) benzo[1,3]dioxole-5,6-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 5,6-dinitro-benzo[1,3]dioxole [Reference Example 56(b)] there wasprepared benzo[1,3]dioxole-5,6-diamine as an oily solid. LC-MS (METHODB): R_(T)=0.43 minutes, 153.18 (M+H)⁺.

(q) 4,5-dimethoxybenzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4,5-dimethoxy-2-nitroaniline there was prepared4,5-dimethoxybenzene-1,2-diamine as an oily solid. LC-MS (METHOD B):R_(T)=0.43 minutes, 169.24 (M+H)⁺.

(r) 4,5-diethylbenzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4,5-diethyl-2-nitroaniline [Reference Example 31(f)] there wasprepared 4,5-diethylbenzene-1,2-diamine which was used without futurepurification. LC-MS (METHOD B): R_(T)=2.21 minutes, 165.24 (M+H)⁺.

(s) 4-ethoxy-5-ethyl-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-ethoxy-5-ethyl-2-nitrophenylamine [Reference Example 31(g)]there was prepared 4-ethoxy-5-ethyl-benzene-1,2-diamine.

(t) 4-Ethoxy-3-ethyl-phenylamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 1-ethoxy-2-ethyl-4-nitrobenzene [Reference Example 32(h)] andsubjecting the reaction product to chromatography on silica gel(heptane, ethyl acetate gradient 25-35%) there was prepared4-ethoxy-3-ethyl-phenylamine (0.6 g) as an oil. GS-MS one peak,R_(T)=7.17 minutes. MS 165 (M)⁺.

(u) 4-Methoxy-3-methyl-phenylamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 1-methoxy-2-methyl-4-nitrobenzene [2.7 g, Reference Example 56(a)]there was prepared 4-methoxy-3-methyl-phenylamine (2.07 g). R_(F)=0.5[ethyl acetate/n-pentane, 1:1, v/v].

(v) 4-Ethoxy-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-ethoxy-2-nitroaniline (1.5 g) 4-ethoxy-benzene-1,2-diamine (1.02g) as a brown oil. LC-MS (Method J): R_(T)=0.50 and 3.88 minutes, 153.30(M+H)⁺.

(w) 4-Fluoro-5-methyl-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-fluoro-5-methyl-2-nitro-phenylamine [Reference Example 31(1)]there was prepared 4-fluoro-5-methyl-benzene-1,2-diamine (1.27 g) as ayellow solid. LC-MS (METHOD J): R_(T)=1.93 minutes, 141.25 (M+H)⁺.

(x) 3,4-Diamino-N-benzyl-benzenesulfonamide

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-amino-N-benzyl-3-nitro-benzenesulfonamide [Reference Example 61]there was prepared 3,4-diamino-N-benzyl-benzenesulfonamide (0.350 g) asa yellow film. LC-MS (METHOD K): R_(T)=2.87 minutes, 278.28 (M+H)⁺.

(y) 4-Difluoromethoxy-benzene-1,2-diamine

By proceeding in a manner similar to Reference Example 30(a) above butusing 4-difluoromethoxy-2-nitro-phenylamine [Reference Example 31(k)]there was prepared 4-difluoromethoxy-benzene-1,2-diamine (2.70 g) as apale brown solid LC-MS (METHOD N): R_(T)=2.45 minutes, 175 (M+H)⁺.

(z) 4-Ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example30(z)]

By proceeding in a manner similar to Reference Example 30(a) but using5-ethyl-4-methoxy-2-nitro-phenylamine [2.4 g, Reference Example 31(1)]there was prepared 4-ethyl-5-methoxy-benzene-1,2-diamine (1.6 g) as ablack solid. LC-MS (METHOD 1, AMMONIUM ACETATE, 5 min): R_(T)=3.50minutes, 167.17 (M+H)⁺.

(aa) 3-Ethyl-4-methoxy-phenylamine

By proceeding in a manner similar to Reference Example 30(a) but using5-ethyl-4-methoxy-2-nitro-phenylamine [3.6 g, Reference Example 31 (1)]and carrying out the reaction for 24 hours, there was prepared3-ethyl-4-methoxy-phenylamine (2.5 g) as a brown oil. LC-MS (METHOD J):R_(T)=2.04 minutes, 152.2 (M+H)⁺.

REFERENCE EXAMPLE 31 (a) 5-Ethyl-2-nitro-aniline

A stirred solution of sodium methoxide (0.35 g) in methanol (15 ml) wastreated with a solution of 4-ethyl-2-nitro-N-acetyl-aniline [1 g,Reference Example 32(a)] in methanol (15 ml). The reaction mixture wasstirred at room temperature for 24 hours and then poured onto ice-water.The resulting precipitate was filtered and then dried to give5-ethyl-2-nitro-aniline (650 mg). LC-MS (METHOD B): R_(T)=3.11 minutes;167.2 (M+H)⁺.

(b) 4-Ethyl-5-methyl-2-nitro-aniline

By proceeding in a manner similar to Reference Example 31 (a) above butusing 4-ethyl-5-methyl-2-nitro-N-acetyl-aniline [1 g, Reference Example32(b)] there was prepared 4-ethyl-5-methyl-2-nitro-aniline as a orangesolid. LC-MS (METHOD B): R_(T)=3.16 minutes; 181.14 (M+H)⁺.

(c) 4-isopropyl-5-methyl-2-nitro-aniline

By proceeding in a manner similar to Reference Example 31(a) above butusing 4-isopropyl-5-methyl-2-nitro-N-acetyl-aniline [1 g, ReferenceExample 32(c)] there was prepared 4-isopropyl-5-methyl-2-nitro-anilineas an orange solid. LC-MS (METHOD B): R_(T)=3.26 minutes; 195.3 (M+H)⁺.

(d) 4-bromo-5-methyl-2-nitro-aniline

By proceeding in a manner similar to Reference Example 31 (a) above butusing 4-bromo-5-methyl-2-nitro-N-acetyl-aniline [1 g, Reference Example32(d)] there was prepared 4-bromo-5-methyl-2-nitro-aniline as a brownsolid. LC-MS (METHOD B): R_(T)=3.24 minutes; 231.2 (M+H)⁺.

(e) 4-n-Propyl-2-nitro-aniline

By proceeding in a manner similar to Reference Example 31 (a) above butusing 2-nitro-4-propyl-N-acetyl-aniline there was prepared4-n-propyl-2-nitro-aniline as an orange solid.

LC-MS (Method C): R_(T)=3.46 minutes; 181.2 (M+H)⁺.

(f) 4,5-diethyl-2-nitro-aniline

By proceeding in a manner similar to Reference Example 31 (a) above butusing 4,5-diethyl-2-nitro-N-acetyl-aniline [Reference Example 32(f)]there was prepared 4,5-diethyl-2-nitro-aniline.

LC-MS (METHOD B): R_(T)=3.27 minutes; 195.22 (M+H)⁺.

(g) 4-Ethoxy-5-ethyl-2-nitrophenylamine

N-4-Ethoxy-5-ethyl-2-nitrophenyl)acetamide [0.2 g, Reference Example32(g)] was dissolved in ethanol (25 mL) and sodium hydride (100 mg, 50%dispersion in mineral oil, 2 mmol) was added. Mixture was stirredovernight at ambient temperature, aq ammonium chloride (3 mL) was addedand the mixture was evaporated. The residue was chromatographed onsilica gel (heptane with gradient of 25-50% ethyl acetate) to give4-ethoxy-5-ethyl-2-nitrophenylamine (0.1 g) as a red solid. LC-MS(Method E): R_(T)=3.4 minutes, 211 (M+H)⁺.

(h) 5-Chloro-4-methoxy-2-nitrophenylamine

N-(5-Chloro-4-methoxy-2-nitrophenyl)acetamide (8.0 g, Reference Example32(i) was added to a solution of sodium methoxide (2.0 g, 0.037 mole) inmethanol (150 mL) and the mixture was stirred at ambient temperature for4 hours. The reaction mixture was added to ice water (750 mL), stirredfor 15 minutes and the aqueous mixture was filtered. The precipitate waswashed with water and dried at 60° C. under vacuum to give5-chloro-4-methoxy-2-nitrophenylamine (6.52 g) as an orange solid, mp128-129° C.

(i) 4-Methoxy-5-methyl-2-nitro-phenylamine

By proceeding in a manner similar to Reference Example 31 (a) above butusing N-(4-methoxy-5-methyl-2-nitro-phenyl)-acetamide [2.53 g, ReferenceExample 32(j)] there was prepared 4-methoxy-5-methyl-2-nitro-phenylamine(2.05 g) as a bright orange solid. LC-MS (Method J): R_(T)=3.46 minutes,183.29 (M+H)⁺.

(j) 4-Fluoro-5-methyl-2-nitro-phenylamine

By proceeding in a manner similar to Reference Example 31 (a) above butusing N-(4-fluoro-5-methyl-2-nitro-phenyl)-acetamide [2.53 g, ReferenceExample 32(k)] there was prepared 4-fluoro-5-methyl-2-nitro-phenylamine(2.25 g) as an orange solid. LC-MS (METHOD J): R_(T)=3.53 minutes,171.28 (M+H)⁺.

(k) 4-difluoromethoxy-2-nitro-phenylamine

By proceeding in a manner similar to Reference Example 31 (a) above butusing N-(4-difluoromethoxy-2-nitro-phenyl)-acetamide [Reference Example32(1)] there was prepared 4-difluoromethoxy-2-nitro-phenylamine (10 g)as an orange solid. LC-MS (METHOD N): R_(T)=3.86 minutes, 205 (M+H)⁺.

(l) 5-Ethyl-4-methoxy-2-nitro-phenylamine

By proceeding in a manner similar to Reference Example 31(a) but usingN-(5-ethyl-4-methoxy-2-nitro-phenyl)-acetamide [2.4 g, Reference Example32(m)] there was prepared 5-ethyl-4-methoxy-2-nitro-phenylamine (1.9 g)as a brown solid. LC-MS (METHOD K): R_(T)=4.14 minutes, 197.09 (M+H)⁺.

REFERENCE EXAMPLE 32 (a) 4-Ethyl-2-nitro-N-acetyl-aniline

A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example33(a)] in acetic anhydride (8 mL) and acetic acid (4 mL), at −5° C., wastreated dropwise with a mixture of acetic acid (1.75 mL) andconcentrated nitric acid (1.22 mL). The mixture was warmed to 0° C.,then stirred at 0° C. for 2 hours and then poured onto water. Thismixture was evaporated and the resulting oil was partitioned betweenethyl acetate and water. The organic layer was dried over magnesiumsulfate and then evaporated. The residual oil was subjected to flashcolumn chromatography on silica eluting with a mixture of ethyl acetateand petroleum ether (2:5) to give 4-ethyl-2-nitro-N-acetyl-aniline (1.4g) as an orange solid. LC-MS (METHOD B): R_(T)=2.95 minutes; 209.2(M+H)⁺.

(b) 4-Ethyl-5-methyl-2-nitro-N-acetyl-aniline

By proceeding in a manner similar to Reference Example 32(a) above butusing 3-methyl-4-ethyl-N-acetyl aniline there was prepared4-ethyl-5-methyl-2-nitro-N-acetyl-aniline as a orange solid.

LC-MS (METHOD B): R_(T)=3.03 minutes; 223.25 (M+H)⁺.

(c) 4-isopropyl-5-methyl-2-nitro-N-acetyl-aniline

By proceeding in a manner similar to Reference Example 32(a) above butusing 3-methyl-4-isopropyl-N-acetyl aniline [Reference Example 33(b))]there was prepared 4-isopropyl-5-methyl-2-nitro-N-acetyl-aniline as anorange solid. LC-MS (METHOD B): R_(T)=3.15 minutes; 231.36 (M+H)⁺.

(d) 4-Bromo-5-methyl-2-nitro-N-acetyl-aniline

By proceeding in a manner similar to Reference Example 32(a) above butusing 3-methyl-4-bromo-N-acetyl aniline [Reference Example 33(c)] therewas prepared 4-bromo-5-methyl-2-nitro-N-acetyl-aniline as an orangesolid. LC-MS (METHOD B): R_(T)=3.06 minutes; 274.2 (M+H)⁺.

(f) 4,5-Diethyl-2-nitro-N-acetyl-aniline

By proceeding in a manner similar to Reference Example 32(a) above butusing 3,4-diethyl-N-acetyl aniline [Reference Example 33(d)] there wasprepared 4,5-diethyl-2-nitro-N-acetyl-aniline as an orange solid. LC-MS(METHOD B): R_(T)=3.18 minutes; 237.4 (M+H)⁺.

(g) N-(4-Ethoxy-5-ethyl-2-nitrophenyl)acetamide

N-(4-Ethoxy-3-ethyl-phenyl) acetamide [3.1 g, Reference Example 33(e)]was dissolved in acetic anhydride (5 mL), a solution of nitric acid inacetic acid (0.5 mL of 95% nitric acid, in 4 mL) was added and themixture was stirred overnight at ambient temperature. The mixture wasdiluted with water (100 mL) and the aqueous mixture was extracted twicewith ethyl acetate (100 mL). The combined extracts were evaporated andthe residue was chromatographed on silica gel (heptane/ethyl acetate9/1) to give N-(4-ethoxy-5-ethyl-2-nitrophenyl)acetamide (3.0 g) as abright yellow solid. LC-MS (Method E): R_(T)=3.27 minutes, 253 (M+H)⁺.

(h) 1-Ethoxy-2-ethyl-4-nitrobenzene

A solution of 1-ethoxy-2-ethyl benzene (3.5 g, Reference Example 51) inacetic anhydride (30 mL) was chilled in an ice-water bath. A solution ofnitric acid (1.4 mL of 90%-30% excess) in acetic acid (25 mL) was addeddropwise and the mixture was stirred overnight at ambient temperature.The reaction mixture was poured into ice water (300 mL) and the aqueousmixture was extracted with ethyl acetate (2×200 mL). The combinedextracts were evaporated and the residue was chromatographed on silicagel (heptane with gradient of 5 to 10% ethyl acetate) to give1-ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a clear liquid. LC-MS (MethodE) R_(T)=3.75 minutes, 196 (M+H)⁺.

(i) N-(5-Chloro-4-methoxy-2-nitrophenyl)acetamide

A solution of N-3-chloro-4-methoxyphenyl)acetamide (6.85 g, ReferenceExample) in a mixture of acetic acid (20 mL) and acetic anhydride (35mL) was cooled to −5° C. and a solution of fuming nitric acid (3 mL) inacetic acid (4 mL) was added dropwise keeping the reaction temperaturebelow 0° C. The mixture was stirred at 0° C. for 30 minutes at whichpoint a yellow precipitate developed. After another 1.5 h at 0° C., themixture was poured into water (100 mL) and the aqueous mixture wasvigorously stirred for 15 minutes and filtered. The yellow precipitatewas washed with water and dried under vacuum at 60° C. to give theproduct (8.0 g) as a yellow solid, mp 152-153° C. MS 245 (M+H)⁺.

(j) N-(4-Methoxy-5-methyl-2-nitro-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 32(a) but usingN-(4-methoxy-3-methyl-phenyl)-acetamide [2.65 g, Reference Example33(f)] there was preparedN-(4-methoxy-5-methyl-2-nitro-phenyl)-acetamide (2.53 g) as a orangesolid. LC-MS (Method J): R_(T)=3.30 minutes, 225.29 (M+H)⁺, 223.29(M−H)⁻.

(k) N-(4-Fluoro-5-methyl-2-nitro-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 32(a) above butusing N-(4-fluoro-3-methyl-phenyl)-acetamide [2.65 g, Reference Example33(g)] there was prepared N-(4-fluoro-5-methyl-2-nitro-phenyl)-acetamide(2.25 g) as a yellow solid. LC-MS (METHOD J): R_(T)=3.31 minutes, 211.26(M−H)⁻

(l) N-(4-Difluoromethoxy-2-nitro-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 32(a) above butusing N-4-diflluoromethoxy-phenyl)-acetamide [Reference Example 33(h)]there was prepared N-(4-difluoromethoxy-2-nitro-phenyl)acetamide (450mg) as a yellow solid. LC-MS (METHOD K): R_(T)=3.72 minutes, MS: 245(M−H)⁻.

(m) N-(5-Ethyl-4-methoxy-2-nitro-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 32(a) but usingN-(3-ethyl-4-methoxy-phenyl)-acetamide [2.9 g, Reference Example 33(i)]there was prepared N-(5-Ethyl-4-methoxy-2-nitro-phenyl)-acetamide (2.4g) as a yellow solid. LC-MS (METHOD K): R_(T)=4.04 minutes, MS: 239.16(M+H)⁺.

REFERENCE EXAMPLE 33 (a) 4-Ethyl-N-acetyl-aniline

A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 mL)in dichloromethane (40 mL) at 0° C. under nitrogen was treated dropwisewith acetic anhydride (4.67 mL). The mixture was warmed to ambienttemperature, then stirred for 16 hours at room temperature, then washedwith (i) 10% citric acid (40 mL), (ii) water (40 mL) and (iii) brine (40mL). The organic phase was dried over magnesium sulfate and thenevaporated to give 4-ethyl-N-acetyl-aniline (2.36 g) as a pale orangesolid which was used without further purification. LC-MS (METHOD B):R_(T)=2.80 minutes; 164.2 (M+H)⁺.

(b) 3-Methyl-4-isopropyl-N-acetyl aniline

By proceeding in a manner similar to Reference Example 33(a) above butusing 3-methyl-4-isopropylaniline there was prepared3-methyl-4-isopropyl-N-acetyl aniline as an orange solid. LC-MS (METHODB): R_(T)=2.97 minutes; 192.3 (M+H)⁺.

(c) 3-Methyl-4-bromo-N-acetyl aniline

By proceeding in a manner similar to Reference Example 33(a) above butusing 3-methyl-4-bromoaniline there was prepared3-methyl-4-bromo-N-acetyl aniline as a brown solid.

LC-MS (METHOD B): R_(T)=2.88 minutes; 228.12 (M+H)⁺.

(d) 3,4-Diethyl-N-acetyl aniline

By proceeding in a manner similar to Reference Example 33(a) above butusing 3,4-diethylaniline there was prepared 3,4-diethyl-N-acetyl anilinewhich was used without further purification.

LC-MS (METHOD B): R_(T)=3.03 minutes; 192.30 (M+H)⁺.

(e) N-(4-Ethoxy-3-ethyl-phenyl) acetamide

To a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example30(t)] in pyridine (5 mL) was added acetic anhydride (1 mL) and themixture was stirred 18 hours at ambient temperature. The reactionmixture was diluted with water (1000 mL) and the aqueous mixture wasextracted twice with ethyl acetate (100 mL). The combined extracts wereevaporated to give N-(4-ethoxy-3-ethyl-phenyl) acetamide (0.6 g) as apink foam. GC-MS one peak, R_(T)=9.16 minutes, MS 207 (M)⁺.

(f) N-(4-Methoxy-3-methyl-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 33(a) above butusing 4-methoxy-3-methyl-phenylamine (2.07 g, Reference Example 30(u))and subjecting the reaction product to flash chromatography on silicaeluting with a mixture of ethyl acetate and n-pentane (1:1, v/v) therewas prepared N-4-methoxy-3-methyl-phenyl)-acetamide (2.65 g) as a palepink crystalline solid. LC-MS (Method J): R_(T)=2.94 minutes, 180.30(M+H)⁺.

(g) N-(4-Fluoro-3-methyl-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 33(a) above butusing 4-fluoro-3-methylaniline there was preparedN-(4-fluoro-3-methyl-phenyl)-acetamide (3.82 g) as an orange solid.LC-MS (METHOD J): R_(T)=3.08 minutes, 168.24 (M+H)⁺.

(h) N-(4-Diflluoromethoxy-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 33(a) above butusing 4-difluoromethoxyaniline there was preparedN-(4-diflluoromethoxy-phenyl)-acetamide (5.90 g) as an orange solid.LC-MS (METHOD K): R_(T)=3.62 minutes, 202 (N+H)⁺.

(i) N-(3-Ethyl-4-methoxy-phenyl)-acetamide

By proceeding in a manner similar to Reference Example 33(a) but using3-ethyl-4-methoxy-phenylamine [2.5 g, Reference Example 30(aa)] therewas prepared N-(3-ethyl-4-methoxy-phenyl-acetamide (2.9 g) was preparedas a light brown solid. LC-MS (METHOD K): R_(T)=3.92 minutes, 194.16(M+H)⁺.

REFERENCE EXAMPLE 34 (a) 4′-Amino-3′-nitro-biphenyl-3-carbonitrile

A stirred solution of 3-cyanophenyl boronic acid (812 mg) andtetrakis(triphenylphosphine) palladium (150 mg) in tetrahydrofuran (4mL) under at atmosphere of nitrogen was treated with4-bromo-2-nitroaniline in tetrahydrofuran (10 mL). The reaction mixturewas heated at 85° C. for 48 hours, then cooled to ambient temperatureand then partitioned between ethyl acetate and water. The organic layerwas washed with brine, then dried over magnesium sulfate and thenevaporated. The residue was subjected to flash column chromatography onsilica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) togive 4′-amino-3′-nitro-biphenyl-3-carbonitrile (224 mg) as a yellowsolid. LC-MS (METHOD B): R_(T)=3.21 minutes, 240.3 (M+H)⁺.

(b) 2-nitro-4-pyridine-3-yl-phenylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing pyridine-3-boronic acid there was prepared2-nitro-4-pyridine-3-yl-phenylamine as a yellow solid. LC-MS (METHOD B):R_(T)=2.09 minutes, 216.24 (M+H)⁺.

(c) 2-methyl-5-nitro-biphenyl-4-yl amine

By proceeding in a manner similar to Reference Example 34(a) above butusing phenyl boronic acid and 4-bromo-5-methyl-2-nitro-aniline[Reference Example 31(d)] there was prepared2-methyl-5-nitro-biphenyl-4-yl amine as an orange solid. LC-MS (METHODB): R_(T)=3.30 minutes, MS: 229.23 (M+H)⁺.

(d) 3-nitrophenyl-4-ylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing phenyl boronic acid there was prepared 3-nitrophenyl-4-ylamine asa red solid. LC-MS (METHOD B): R_(T)=3.43 minutes, 215.06 (M+H)⁺.

(e) 2′-fluoro-3-nitro-biphenyl-4-ylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing 2-fluorophenyl boronic acid there was prepared2′-fluoro-3-nitro-biphenyl-4-ylamine as a red solid. LC-MS (METHOD B):R_(T)=3.33 minutes, 233.3 (M+H)⁺.

(f) 4′-benzo[1,3]dioxo-5-yl-2-nitrophenylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing 3,4-methylenedioxyphenyl boronic acid there was prepared4′-benzo[1,3]dioxo-5-yl-2-nitrophenylamine as a orange solid. LC-MS(METHOD B): R_(T)=3.23 minutes, 259.3 (M+H)⁺.

(g) 2′-methoxy-3-nitro-biphenyl-4-ylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing 2-methoxyphenyl boronic acid there was prepared2′-methoxy-3-nitro-biphenyl-4-ylamine as an orange solid. LC-MS (METHODB): R_(T)=3.30 minutes, 245.3 (M+H)⁺.

(h) 4′-chloro-3-nitro-biphenyl-4-ylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing 4-chlorophenyl boronic acid there was prepared4′-chloro-3-nitro-biphenyl-4-ylamine as an orange solid. LC-MS (METHODB): R_(T)=3.45 minutes, 249.27 (M+H)⁺.

(i) 4′-methyl-3-nitro-biphenyl-4-ylamine

By proceeding in a manner similar to Reference Example 34(a) above butusing 4-methylphenyl boronic acid there was prepared4′-methyl-3-nitro-biphenyl-4-ylamine as an orange solid. LC-MS (METHODB): R_(T)=3.33 minutes, 229.2 (M+H)⁺.

REFERENCE EXAMPLE 35 (a) 4-benzyloxy-1,2-dinitrobenzene

A stirred solution of 3,4-dinitrophenol (1 g) in dimethylformamide (30mL) was treated with benzyl bromide (723 μL) and potassium carbonate(1.13 g). The reaction mixture was stirred at ambient temperature for 24hours and then partitioned between ethyl acetate and water. The organiclayer was washed with brine, then dried over magnesium sulfate and thenevaporated. The residue was subjected to flash column chromatography onsilica eluting with a mixture of ethyl acetate and hexane (1:4, v/v) togive 4-benzyloxy-1,2-dinitrobenzene (1.30 g) as a yellow solid. LC-MS(METHOD B): R_(T)=3.31 minutes. ¹HNMR [(CD₃)₂CO, ppm): δ 5.28 (s, 2H),7.26-7.42 (m, 61), 7.57 (d, 1H), 8.12 (d, 1H).

(b) 1-Ethyl-2-methoxy-benzene

By proceeding in a manner similar to Reference Example 35(a) above, butusing 2-ethylphenol (5 ml) and iodomethane (2.6 ml) with acetone assolvent and heating at 70° C. for 24 hours in a sealed pressure vessel,there was prepared 1-ethyl-2-methoxy-benzene (5.6 g) as a yellow oilwhich was used without future purification. LC-MS (METHOD K): R_(T)=3.83minutes. I H NMR (d₆ acetone): δ 6.95 (m, 2H), 6.75 (d, 1H), 6.68 (t,1H), 3.67 (s, 3H), 2.44 (q, 2H) 0.95 (t, 3H).

REFERENCE EXAMPLE 36 (a) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4,5-dimethylphenyl)amide

Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) anddiisopropylethylamine (30 ml) in dichloromethane (200 ml) was treatedwith 4-nitropyrazole-3-carboxylic chloride (5 g) portionwise at 0° C.The reaction mixture was warmed to ambient temperature and stirred for30 minutes. The solvent was removed in vacuo and the oily residue waspartitioned between ethyl acetate and water. The organic layer was driedover magnesium sulfate and concentrated. The residual oil wasre-crystallised from ethyl acetate and methanol (10%) to give4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide(6.58 g) as an orange solid. LC-MS (METHOD B): R_(T)=2.36 minutes,276.09 (M+H)⁺.

Method B Polyphosphoric acid (500 g) was added to a 1 L flask equippedwith an overhead stirrer and heated to 70° C. under nitrogen. A blendedmixture of 4-nitro-3-pyrazole carboxylic acid (50 g) and1,2-diamino-4,5-dimethylbenzene (43.4 g) was added and the mixture washeated to 180° C. After 1 hour at this temperature the reaction mixturewas cooled to 130° C. and poured into ice water (2.5 kg). This mixturewas stirred with an overhead stirrer and then treated with aqueousammonium hydroxide (350 mL, 30%) until the pH was 2.1. After stirringfor a further 15 minutes the mixture was filtered and the filtered solidwas washed three times with water (200 mL) then dried under vacuum togive 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4,5-dimethylphenyl)amide as a brown solid.

(b) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-ethyl-5-methylphenyl)amide

By proceeding in a manner similar to Reference Example 36(a), Method A,above but using 4-ethyl-5-methyl-phenylene diamine [Reference Example30(a)] there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-ethyl-5-methylphenyl)amide as a dark red solid. LC-MS (METHODB): R_(T) 2.89 minutes, 290.24 (M+H)⁺.

(c) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-5-chloro-4-methoxyphenyl)amide

By proceeding in a manner similar to Reference Example 36(a), Method A,above but using 4-chloro-5-methoxybenzene-1,2-diamine [1 g, ReferenceExample 49(b)], diisopropylethylamine (4.1 mL, 4 eq), dichloromethane(50 mL) and a solution of 4-nitropyrazole-3-carbonyl chloride (1 g, 5.8mmol) in dichloromethane (25 mL) and stirring the reaction mixture atambient temperature for 18 hours there was prepared a mixture of4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-5-chloro-4-methoxyphenyl)amide and the bis-acylated material,MS 310 (M⁻) and 449 (M⁻). This material was used without furtherpurification in Example 20(c).

(d) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-methoxy-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(a), Method A,above but using 4-methoxy-1,2-phenylenediamine (880 mg) and4-nitropyrazole-3-carboxylic chloride [prepared by treating a solutionof 4-nitropyrazole-3-carboxylic acid (1 g) in dry dichloromethane (70ml) under nitrogen with oxalyl chloride (1.11 ml) and dimethylformamideand after stirring overnight evaporating the reaction mixture thenazeotroping three times with toluene (10 ml)] there was prepared4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl)-amide(800 mg). LC-MS (Method J): R_(T)=2.67 minutes, 278.25 (M+H)⁺, 276.28(M−H)⁻.

(e) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-ethoxy-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(d) above butusing 4-ethoxy-benzene-1,2-diamine [1.25 g, Reference Example 30(v)] andsubjecting the reaction product to flash chromatography on silica,eluting initially with ethyl acetate and then with a mixture of ethylacetate and methanol (9:1, v/v), there was prepared4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl)-amide(824 mg) a black solid. LC-MS (Method J): R_(T)=2.90 minutes, 292.27(M+H)⁺, 290.30 (M−H)⁻.

(f) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-fluoro-5-methyl-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(d) above butusing 4-fluoro-5-methyl-benzene-1,2-diamine [Reference Example 30(w)]there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-fluoro-5-methyl-phenyl)-amide (20.12 g) as a red oil. LC-MS(METHOD J): R_(T)=3.02 minutes, 280.25 (M+H)⁺.

(g) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethoxy-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(d) above butusing 4-trifluoromethoxy-benzene-1,2-diamine [Reference Example 30(x)]there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethoxy-phenyl)-amide (0.850 g) as a red solid.LC-MS (METHOD J): R_(T)=3.34 minutes, 332.21 (M+H)⁺.

(h) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethyl-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(d) above butusing 4-trifluoromethyl-benzene-1,2-diamine [Reference Example 30(y)]there was prepared 4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-trifluoromethyl-phenyl)-amide (0.250 g) as an red solid.LC-MS (METHOD B): R_(T)=3.35 minutes, 316.14 (M+H)⁺.

(i) 4-Nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-chloro-5-methyl-phenyl)-amide

By proceeding in a manner similar to Reference Example 36(d) above butusing 4-chloro-5-methyl-benzene-1,2-diamine there was prepared4-nitro-1H-pyrazole-3-carboxylic acid(2-amino-4-chloro-5-methyl-phenyl)-amide (0.300 g) as a yellow solid.LC-MS (METHOD B): R_(T)=2.72 minutes, 296.10 (M+H)⁺.

(j) 3-Amino-4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-benzoic acidmethyl ester

By proceeding in a manner similar to Reference Example 36(d) above butusing methyl-3,4-diaminobenzoate there was prepared3-amino-4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-benzoic acid methylester (2.51 g) as a tan foam solid. LC-MS (METHOD B): R_(T)=2.83minutes, 306.21 (M+H)⁺.

REFERENCE EXAMPLE 37 5-Ethoxy-1H-indazole

A solution of 5-hydroxy-1H-indazole [0.5 g, Reference Example 38] inacetone (10 ml) was treated with potassium carbonate (2.56 g) then withiodoethane (0.296 ml). The mixture was refluxed for 4 hours then cooledand then evaporated. The residue was partitioned between ethyl acetateand water and the aqueous layer was further extracted twice with ethylacetate. The combined organic fractions were dried over magnesiumsulfate and then evaporated to yield a brown residue which was subjectedto flash column chromatography on silica eluting with a mixture of ethylacetate and hexane (1:1, v/v) to give 5-ethoxy-1H-indazole (0.38 g) asan off-white solid. LC-MS (METHOD B): R_(T)=2.68 minutes; 163 (M+H)⁺.

REFERENCE EXAMPLE 38 5-Hydroxy-1H-indazole

A solution of 5-methoxy-1H-indazole [0.410 g, Reference Example 24(a)]in dichloromethane (7.5 ml) was treated with a solution of borontribromide in dichloromethane (7.5 ml, 1M). The mixture was then heatedto reflux for 4 hours, then cooled to 0° C. and then treated dropwisewith water (2 ml). The pH of this mixture was adjusted to 7-8 byaddition of 10% aqueous sodium hydrogen carbonate. The mixture was thenextracted three times with ethyl acetate. The combined extracts weredried over magnesium sulfate and then evaporated. The residual brown oilwas subjected to flash column chromatography on silica eluting with amixture of ethyl acetate and hexane (1:1, v/v) to give5-hydroxy-1H-indazole (0.310 g) as a yellow solid. LC-MS (METHOD B):R_(T)=1.96 minutes; 135 (M+H)⁺.

REFERENCE EXAMPLE 39 (a)1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid,3-(2-amino-4,5-dimethylphenyl)amide, 5-tert-butyl ester

To a solution of 4,5-dimethylbenzene-1,2-diamine (0.841 g) and1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester [1.5 g, Reference Example 40(a)] in dimethylformamide (100 ml) was added diisopropylethylamine (1.08 ml) and2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (2.35 g). The mixture was stirred for 1.5 hours anddiluted with ethyl acetate then washed six times with brine. The organiclayer was dried over magnesium sulfate and concentrated in vacuo toyield a pale brown solid. The solid was then triturated with methanol toyield 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid,3-(2-amino-4,5-dimethylphenyl)amide, 5-tert-butyl ester (0.99 g) as anoff-white solid. LC-MS (METHOD B): R_(T) 2.94 minutes; 386 (M+H)⁺.

(b) Morpholine-4-carboxylic acid[3-(2-amino-4,5-dimethyl-phenylcarbamoyl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylmethyl]-(2,4-dimethoxy-benzyl)-amide

By proceeding in a manner similar to Reference Example 39(a) above butusing4-{[(2,4-dimethoxy-benzyl)-morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid [534 mg, Reference Example 40(b)] there was preparedmorpholine-4-carboxylic acid[3-(2-amino-4,5-dimethyl-phenylcarbamoyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylmethyl]-(2,4-dimethoxy-benzyl)-amide(1.66 g) as a yellow oil. LC-MS (METHOD B): R_(T)=2.81 minutes, 607.71(M+H)⁺.

(c)3-(2-Amino-4-chloro-5-methyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Reference Example 39(a) above butusing 4-chloro-5-methyl-1,2-phenylenediamine there was prepared3-(2-amino-4-chloro-5-methyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (411 mg) as a brown solid. LC-MS (METHOD 3):R_(T)=3.66 minutes, 406/408 (M+H)⁺.

(d)3-[2-Amino-4-(2-morpholin-4-yl-ethoxy)-phenylcarbamoyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Reference Example 39(a) above butusing 4-2-morpholin-4-yl-ethoxy)-benzene-1,2-diamine [Reference Example29(c)] there was prepared3-[2-amino-4-(2-morpholin-4-yl-ethoxy)-phenylcarbamoyl]-14,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (400 mg) as a brown solid. LC-MS (METHOD N):R_(T)=3.33 minutes, 485.18 (M−H)⁻.

(e) 1,4,6,7-Tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid(2-amino-4,5-dimethyl-phenyl)-amide

By proceeding in a manner similar to Reference Example 39(a) above butusing 1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid[Reference Example 17(e)] there was prepared1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole-3-carboxylic acid(2-amino-4,5-dimethyl-phenyl)-amide (116 mg) as a cream solid. LC-MS(METHOD B): R_(T)=2.32 minutes, 287 (M+H)⁺.

(f)3-(2-Amino-4-trifluoromethyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester

By proceeding in a manner similar to Reference Example 39(a) above butusing 4-trifluoromethyl-1,2-phenylenediamine there was prepared3-(2-amino-4-trifluoromethyl-phenylcarbamoyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid tert-butyl ester (1.00 g) as a brown solid. LC-MS (METHOD N):R_(T)=3.75 minutes, 424.10 (M−H)⁻.

REFERENCE EXAMPLE 40 (a)1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester

A solution of1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester 3-ethyl ester [5.105 g, Reference Example 18(d)] andlithium hydroxide monohydrate (0.870 g) in methanol (30 ml) and water(10 ml) was stirred at 55° C. for 2.5 hours. The mixture was acidifiedwith saturated aqueous potassium hydrogen sulfate solution and extractedthree times with ethyl acetate. The organic extracts were combined,dried over magnesium sulfate and concentrated in vacuo to yield1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid5-tert-butyl ester (4.442 g) as a pale yellow solid. MS: 268 (M+H)⁺.HPLC (METHOD G): R_(T)=2.86 minutes.

(b)4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid

By proceeding in a manner similar to Reference Example 40(a) above butusing4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid ethyl ester [594 mg, Reference Example 48(i)] there was prepared4-r[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid (534 mg) as a white fluffy solid. LC-MS (Method B): R_(T)=2.71minutes, 489.21 (M+H)⁺.

REFERENCE EXAMPLE 41 (a) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acidethyl ester

A solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethylester [3.46 g, Reference Example 42] in dichloromethane (25 ml) wastreated with trifluoroacetic acid (25 ml). The mixture was stirred for1.5 hours and then concentrated. The residue was partitioned betweensaturated sodium carbonate solution and ethyl acetate. The organic layerwas dried over magnesium sulfate and then evaporated to give3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.49 g) as abrown solid which was used without further purification. LC-MS (METHODB): R_(T)=2.54 minutes; 171 (M+H)⁺.

(b) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide

By proceeding in a manner similar to Reference Example 41 (a) above butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide[Reference Example 44(a)] there was prepared3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide as a paleyellow solid, which was used without further purification. LC-MS (METHODB): R_(T)=2.43 minutes; 184 (M+H)⁺.

(c) 3-Hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

By proceeding in a manner similar to Reference Example 41 (a) above butusing 3-tert-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethylester [Reference Example 43] there was prepared3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as aorange solid which was used without further purification. LC-MS (METHODB): R_(T)=2.58 minutes; 185 (M+H)⁺.

(d) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide

By proceeding in a manner similar to Reference Example 41(a) above butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide [Reference Example 44(b)] there was prepared3-hydroxymethyl-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide(398 mg) as an orange oil. LC-MS (METHOD B): R_(T)=1.66 minutes, 222(M+Na)⁺.

(e) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide

By proceeding in a manner similar to Reference Example 41(a) above butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide[Reference Example 44(c)] there was prepared3-hydroxymethyl-1H-pyrazole-4-carboxylic acid propylamide (731 mg) as anorange oil. LC-MS (METHOD B): R_(T)=2.09 minutes, 206 (M+Na)⁺.

(f) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-amide

By proceeding in a manner similar to Reference Example 41(a) above butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-lamide [Reference Example 44(d)] there wasprepared 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-amide (4.10 g) as an orange oil. LC-MS (METHODN): R_(T)=1.89 minutes, 226(M+H)⁺.

(g) 3-Hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

By proceeding in a manner similar to Reference Example 41(a) above butusing 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acidcyclopropylamide [Reference Example 44(e)] there was prepared3-hydroxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (2.48 g)as a white foam. LC-MS (METHOD N): R_(T)=1.85 minutes, 180.15 (M−H)⁻.

REFERENCE EXAMPLE 42 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acidethyl ester

A solution of dimethyl formamide acetal (3.47 ml) and4-tert-butoxy-3-oxo-butyric acid ethyl ester [3.52 g, Reference Example43] in toluene (50 ml) was heated at 65° C. for 2 hours. The mixture wasthen concentrated and the residue redissolved in acetic acid (3 ml). Tothe mixture was added hydrazine hydrate (0.93 ml) and the whole allowedto stir at ambient temperature for 2 hours. The mixture was againconcentrated in vacuo and the residue partitioned between ethyl acetateand 5% aqueous sodium hydrogen carbonate solution. The organic layer wasdried over magnesium sulfate and then concentrated to yield a brown oilwhich was subjected to flash column chromatography on silica elutingwith a mixture of ethyl acetate and petrol (3:7, v/v) to give3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.46 g)as a yellow solid. LC-MS (METHOD B): R_(T)=2.79 minutes; 227 (M+H)⁺.

REFERENCE EXAMPLE 43 4-tert-Butoxy-3-oxo-butyric acid ethyl ester

A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil)in dimethyl formamide (50 ml), at 0° C., was treated dropwise withethyl-4-chloroacetoacetate (5 ml) and then with tert-butyl alcohol (7.08ml). This mixture was maintained at 0° C. for 2 hours, then a further 2hours at ambient temperature and then poured onto 2N hydrochloricacid/ice and then extracted four times with ethyl acetate. The combinedextracts were washed with saturated aqueous sodium hydrogen carbonatesolution, then with water, then with brine, then dried over magnesiumsulfate and then evaporated. The resulting yellow oil was subjected toflash column chromatography on silica eluting with a mixture of ethylacetate and petrol (1:9, v/v) to give 4-tert-butoxy-3-oxo-butyric acidethyl ester (5.20 g) as a yellow oil. TLC (silica, 1:4, v/v ethylacetate/petrol): R_(F)=0.51. NMR (400 MHz, CDCl₃): δ 1.21 (9H, s), 1.28(3H, t), 3.55 (2H, s), 4.19 (2H, q).

REFERENCE EXAMPLE 44 (a) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylicacid isopropylamide

To a solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid[1.520 g, Reference Example 17(d)], hydroxybenzatriazole (3.110 g) anddiisopropyl ethylamine (4.010 m]) in dimethyl formamide (130 ml) wasadded isopropylamine (1.960 ml) followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.420 g).The mixture was heated at 70° C. for 2.5 hours, then diluted with ethylacetate, then washed with water, then with brine, then dried overmagnesium sulfate and then evaporated. The residue was triturated with amixture of ethyl acetate and petrol to yield3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide (652mg) as an off-white solid. LC-MS (METHOD B): 2.99 minutes; 240 (M+H)⁺.

(b) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide

By proceeding in a manner similar to Reference Example 44(a) above butusing 2-methoxyethylamine, there was prepared3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid(2-methoxy-ethyl)-amide (811 mg) as an orange oil. LC-MS (METHOD B):R_(T)=2.43 minutes, 278 (M+Na)⁺.

(c) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide

By proceeding in a manner similar to Reference Example 44(a) above butusing n-propylamine there was prepared3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid propylamide (1.12 g)as an orange oil. LC-MS (METHOD B): R_(T)=2.65 minutes, 262 (M+Na)⁺.

(d) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-lamide

By proceeding in a manner similar to Reference Example 44(a) above butusing tetrahydropyran-4-ylamine there was prepared3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid(tetrahydro-pyran-4-yl)-lamide (5.50 g) as an orange oil. LC-MS (METHODN): R_(T)=3.05 minutes, 282 (M+H)⁺.

(e) 3-tert-Butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide

By proceeding in a manner similar to Reference Example 44(a) above butusing cyclopropylamine there was prepared3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide(3.27 g) as an orange oil. LC-MS (METHOD H): R_(T)=2.24 minutes, 238.38(M+H)⁺.

REFERENCE EXAMPLE 453-tert-Butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a solution of 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester[0.325 g, Reference Example 46] in acetic acid (3 ml) was addedhydrazine hydrate (71 μL). The mixture was stirred at ambienttemperature for 16 hours and then evaporated to remove the acetic acid.The residue was dissolved in ethyl acetate and the solution was washedwith 5% sodium hydrogen carbonate solution, then with water, then driedover magnesium sulfate, and then evaporated to yield3-tert-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester(0.258 g) as a yellow oil which was used without further purification.LC-MS (METHOD B): R_(T)=3.22 minutes; 241 (M+H)⁺.

REFERENCE EXAMPLE 46 2-Acetyl-4-tert-butoxy-3-oxo-butyric acid ethylester

A suspension of dry magnesium chloride (0.471 g) in dichloromethane (6ml) was treated with 4-tert-butoxy-3-oxo-butyric acid ethyl ester [1.00g, Reference Example 43]. This mixture was cooled to 0° C., then treatedwith pyridine (0.80 ml), then stirred for 15 minutes at 0° C. and thentreated with acetyl chloride (0.352 ml). After stirring for a further 15minutes at 0° C. and then for 1 hour at ambient temperature the reactionmixture was treated with saturated aqueous ammonium chloride solutionand then extracted twice with ethyl acetate. The combined extracts weredried over magnesium sulfate and then evaporated to yield2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester (1.15 g) as ayellow oil which was used without further purification. LC-MS (METHODB): R_(T)=3.16 minutes; 243 (M−H)⁻.

REFERENCE EXAMPLE 47 4-Phenyl-1H-pyrazole-3-carboxylic acid

A solution of 3-methyl-4-phenylpyrazole (1.00 g) in tert-butanol (15 ml)and water (25 ml), at 60° C., was treated portionwise potassiumpermanganate (5.47 g). The temperature was then slowly elevated to 90°C. and maintained at that temperature for 5 hours. The mixture was thencooled and filtered through a pad of celite. The filtrate wasconcentrated and the pH was adjusted to 10 to 14 by addition of 5Naqueous sodium hydroxide solution. This mixture was washed twice withethyl acetate. The aqueous layer was then acidified to pH 3 to 5 andthen extracted four times with ethyl acetate. The combined extracts weredried over magnesium sulfate and then evaporated to yield4-phenyl-1H-pyrazole-3-carboxylic acid (0.512 g) as a white solid, whichwas used without further purification. MS: 189 (M+H)⁺. HPLC (METHOD B):R_(T)=2.48 minutes.

REFERENCE EXAMPLE 48 (a) Cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

A solution of3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine[0.3 g, Reference Example 49(a)] and triethylamine (0.8 mL, excess) intetrahydrofuran (20 mL) was treated dropwise with cyclopropanecarbonylchloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours thendiluted with aqueous sodium bicarbonate solution (100 mL) and thenextracted twice with ethyl acetate (100 mL). The combined extracts wereevaporated and the residue was dissolved in tetrahydrofuran (50 mL).This solution was treated with a solution of potassium hydroxide (1.1 g)in ethanol (10 mL) and the mixture was stirred for 2 hours, then pouredinto water (100 mL) and then extracted twice with ethyl acetate (100mL). The combined extracts were evaporated and the residue waschromatographed on silica gel eluting with a mixture of heptane andethyl acetate (1/1, v/v) to give cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamide(0.3 g) as an off-white solid. LC-MS (Method E): R_(T) 2.99 minutes, 424(M+H)⁺.

(b) 4-Methylpiperazine-1-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Reference Example 48(a) above but(i) treating a solution of3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine[302 mg, Reference Example 49(d)] and triethylamine (0.94 g, 10 eq) intetrahydrofuran (10 mL) with 4-methylpiperazine-1-carbonyl chloride (930mg, 4.67 mmol), (ii) stirring the mixture at 45° C. for 4 hours, then at55° C. for 1 hour, (iii) treating the cooled reaction mixture withaqueous sodium bicarbonate (200 mL) and extracting this mixture threetimes with ethyl acetate (100 mL), and (iv) evaporating the combinedextracts and chromatographing the residue on silica gel (ethylacetate/gradient 5-20% methanol) there was prepared4-methylpiperazine-1-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide(189 mg) as a purple solid. LC-MS (Method F): R_(T)=2.28 minutes, 450(M+H)⁺.

(c)1,1-Dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea

By proceeding in a similar manner to Reference Example 48(b) above butusing dimethylcarbamyl chloride (4 eq) there was prepared1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]ureaas a beige foam. LC-MS (Method F): R_(T)=3.22 minutes, 395 (M+H)⁺.

(d) Cyclopropanecarboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Reference Example 48(a) above butusing6-ethoxy-5-fluoro-2[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-yl]-1H-benzimidazole[0.45 g, Reference Example 49(e)] and subjecting the reaction product tochromatography on silica gel (heptane/ethyl acetate, 7/3, v/v) there wasprepared cyclopropanecarboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide(90 mg). LC-MS (Method G): R_(T)=8.1 minutes, 414 (M+H)⁺.

(e) Tetrahydropyran-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazole-4-yl]amide

By proceeding in a similar manner to Reference Example 48(a) above butusing6-ethoxy-5-fluoro-2[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-yl]-1H-benzimidazole[0.45 g, Reference Example 49(e)] and tetrahydropyran-4-carbonylchloride (0.135 g) and subjecting the reaction product to chromatographyon silica gel (heptane/ethyl acetate, 7/3, v/v) there was preparedtetrahydropyran-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazole-4-yl]amide(120 mg). LC-MS (Method G): R_(T)=8.05 minutes, 458 (M+H)⁺.

(f) Morpholine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Reference Example 48(a) above but(i) treating6-ethoxy-5-fluoro-2[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-yl]-1H-benzimidazole[90 mg, Reference Example 49(e)] and diisopropylethylamine (168 mg) intetrahydrofuran (4 mL) with morpholine-4-carbonyl chloride (194 mg) for2 days at ambient temperature, and (ii) subjecting the reaction productto chromatography on silica gel (heptane/ethyl acetate, 2/1, v/v), therewas prepared morpholine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide(140 mg). LC-MS (Method G): R_(T)=7.85 minutes, 459 (M+H)⁺.

(g) Piperidine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide

By proceeding in a similar manner to Reference Example 48(f) above butusing piperidine-1-carbonyl chloride (191 mg) there was preparedpiperidine-4-carboxylicacid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide(127 mg). LC-MS (Method G): R_(T)=8.2 minutes, 457 (M+H)⁺.

(h)3-[6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea

By proceeding in a similar manner to Reference Example 48(f) above butusing diethylcarbamyl chloride (175 mg) there was prepared3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea(110 mg). LC-MS (Method G) R_(T)=7-9 minutes, 445 (M+H)⁺.

(i)4-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid

By proceeding in a similar manner to Reference Example 48(a) above but(i) using4-[(2,4-dimethoxy-benzylamino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid ethyl ester (829 mg, Reference Example 60) and 4-morpholinecarbonylchloride (0.96 ml), and (ii) subjecting the reaction product to flashchromatography on silica eluting with ethyl acetate, there was prepared4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid (595 mg) as a colourless oil. LC-MS (Method B): R_(T)=2.96 minutes,517.30 (M+H)⁺.

(j)3-[3-(5-Difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea

By proceeding in a manner similar to Reference Example 48(a) above butusing3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine[Reference Example 49(g)] and diethylcarbamyl chloride, there wasprepared3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea(220 mg) as a pale brown solid. LC-MS (METHOD K): R_(T)=4.02 minutes,447.27 (M−H)⁻.

(k) Piperidine-1-carboxylic acid[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-amide

By proceeding in a manner similar to Reference Example 48(a) above butusing piperidine-1-carbonyl chloride there was preparedpiperidine-1-carboxylic acid[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-amide(220 mg) as a pale brown solid. LC-MS (METHOD N): R_(T)=4.07 minutes,459.28 (M−H)⁻.

REFERENCE EXAMPLE 49 (a)3-(5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine

A solution of5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole[0.8 g, Reference Example 50(a)] in ethanol (100 mL) was treated withpalladium on carbon (0.1 g, 10%) and mixture was hydrogenated atatmospheric pressure (balloon) for 4 days. The catalyst was filteredoff, the filtrate was evaporated and the residue was chromatographed onsilica gel (ethyl acetate with gradient of 0-10% methanol) to give3-(5-ethoxy-6-ethI-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine(0.3 g) as a solid. LC-MS (Method E): R_(T)=2.15 minutes, 356 (M+H)⁺.

(b) 4-chloro-5-methoxybenzene-1,2-diamine

By proceeding in a similar manner to Reference Example 49 (a) above, butusing 5-chloro-4-methoxy-2-nitrophenylamine [Reference Example 31 (h)]and subjecting the reaction product to chromatography on silica gel(ethyl acetate with gradient of 40% to 0% heptane) there was prepared4-chloro-5-methoxybenzene-1,2-diamine (1.0 g) as an orange solid. MS:173 (M+H)⁺.

(c) 4-ethoxy-5-ethyl-benzene-1,2-diamine

By proceeding in a similar manner to Reference Example 49(a) above, butusing 4-ethoxy-5-ethyl-2-nitrophenylamine [Reference Example 31 (g)] andsubjecting the reaction product to chromatography on silica gel elutingwith ethyl acetate there was prepared4-ethoxy-5-ethyl-benzene-1,2-diamine as a dark solid. LC-MS (Method E):R_(T)=8.434 minutes, 180 (M+H)⁺.

(d)3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a similar manner to Reference Example 49(a) above, but(i) using a solution of2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1,5,6,7-tetrahydro-1,3-diaza-s-indacene[4.1 g, Reference Example 50(b)] in ethanol (120 mL) and 5% palladium oncarbon (320 mg), and (ii) using a Parr hydrogenation apparatus at 60 psifor 18 hours there was prepared3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine(368 mg) as a brown solid. LC (Method G): R_(T)=3.079 minutes, 324(M+H)+ and 346 (M+Na)⁺.

(e)6-Ethoxy-5-fluoro-2[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-yl]-1H-benzimidazole

By proceeding in a similar manner to Reference Example 49(a) above, butusing6-ethoxy-5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-benzimidazole[1.2 g, Reference Example 50(c)] there was prepared6-ethoxy-5-fluoro-2[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-yl]-1H-benzimidazole(1.2 g). LC-MS (Method G): R_(T)=6.74 minutes, 346 (M+H)⁺.

(f) 4-Methanesulfonyl-benzene-1,2-diamine

By proceeding in a similar manner to Reference Example 49(a) above, butusing N*1*-benzyl-4-methanesulfonyl-benzene-1,2-diamine [ReferenceExample 65] there was prepared 4-methanesulfonyl-benzene-1,2-diamine asa white solid. LC-MS (METHOD J): R_(T)=0.98 minutes, 187.32 (M+H)⁺.

(g)3-(5-Difluoromethoxy-1H-benzoimidazol-2-yl-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine

By proceeding in a manner similar to Reference Example 49(a) above butusing5-difluoromethoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole[Reference Example 50(e)], there was prepared3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylamine(730 mg) as a pale brown solid. LC-MS (METHOD N): R_(T)=3.27 minutes,350.29 (M+H)⁺.

REFERENCE EXAMPLE 50(a)-5-Ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole

A mixture of 4-ethoxy-5-ethyl-benzene-1,2-diamine [0.18 g, ReferenceExample 30(s)],4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde [0.225 g,Reference Example 6(m)] and sodium bisulfite (0.12 g, 1.2 mmol) indimethylformamide (10 mL) was heated at 120° C. for 1 hour. The mixturewas cooled, water (100 mL) was added and the aqueous mixture wasextracted with twice ethyl acetate (50 mL). The combined extracts wereevaporated and the residue was chromatographed on silica gel (ethylacetate with gradient of 20-0% heptane) to give5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole(200 mg) as a solid. LC-MS (Method E) R_(T)=2.85 minutes, 386 (M+H)⁺.

(b)2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1,5,6,7-tetrahydro-1,3-diaza-s-indacene

By proceeding in a similar manner to Reference Example 50(a) but usingindane-5,6-diamine (1.05 g, prepared as described by Sui Xiong Cai etel., J. Med. Chem., 1997, 40, pages 730-738) and4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde [2.5 g,Reference Example 6(m)] there was prepared2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1,5,6,7-tetrahydro-1,3-diaza-s-indacenewhich was used without father purification.

(c)6-Ethoxy-5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-benzimidazole

By proceeding in a similar manner to Reference Example 50(a) but using4-ethoxy-5-fluoro-benzene-1,2-diamine (2.2 g, prepared according to themethod of Uchida, et al, Chem. Pharm. Bull. 1989, volume 37, pages 1517to 1523) there was prepared6-ethoxy-5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-benzimidazole.LC-MS (Method G): R_(T)=8.1 minutes, 376 (M+H)⁺.

(d)5-Methoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole

By proceeding in a similar manner to Reference Example 50(a) but using4-methoxy-1,2-phenylenediamine (117 mg) there was prepared5-methoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole(282 mg) as a deep red oil. LC-MS (Method H): R_(T)=2.02 minutes, 344.21(M+H)⁺, 342.24 (M−H)⁻.

(e)5-Difluoromethoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole

By proceeding in a manner similar to Reference Example 50(a) above butusing difluoromethoxy-benzene-1,2-diamine [Reference Example 30(y)] and4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde [ReferenceExample 6(m)], there was prepared5-difluoromethoxy-2-[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole(910 mg) as a pale brown solid. LC-MS (METHOD N): R_(T)=3.40 minutes,380.22 (M+H)⁺.

REFERENCE EXAMPLE 51 1-Ethoxy-2-ethyl benzene

To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triphenylphosphine(15.7 g, 60 mmol) and ethanol (6 mL, excess) in tetrahydrofuran (100 mL)was added dropwise DIAD (12.1 g, 60 mmol). After stirring for 18 hours,mixture was evaporated and the residue was chromatographed on silica gel(heptane/ethyl acetate 9/1) to give 1-ethoxy-2-ethyl benzene (7.2 g) asa clear liquid. GC-MS shows one peak, R_(T)=5.6 minutes. MS 150 (M+).

REFERENCE EXAMPLE 52 N-(3-Chloro-4-methoxyphenyl)acetamide

A solution of 3-chloro-4-methoxyphenylamine (6.3 g) and triethylamine(4.04 g) in dichloromethane (100 mL) was chilled in an ice bath, acetylchloride (3.45 g) was added dropwise and the mixture was stirred atambient temperature overnight. The reaction mixture was extracted withwater (2×30 mL) and brine (2×30 mL) and the organic layer was dried withmagnesium sulfate. The drying agent was removed by filtration and thefiltrate was evaporated to give N-(3-chloro-4-methoxyphenyl)acetamide(7.45 g) as a dark oil, which solidified on standing. MS: 200 (M+H)⁺.

REFERENCE EXAMPLE 53[4-Nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol

A stirred solution of4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methylester [500 mg, Reference Example 54(a)] in tetrahydrofuran (20 ml) undernitrogen at −78° C. was treated dropwise with a solution ofdiisobutylaluminium hydride in tetrahydrofuran (8.82 ml, 1M). Thereaction mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was taken up in diethyl ether (100 ml) and quenchedwith water (150 ml). The resulting suspension was filtered throughcelite and the organic layer was collected from the filtrate, then driedover magnesium sulfate and then evaporated to yield[4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol (349 mg) asa peach oil. LC-MS (Method H): R_(T)=2.08 minutes, 250.29 (M+H+ Na)⁺.

REFERENCE EXAMPLE 54 (a)4-Nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methylester

A suspension of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3g, Reference Example 55) and p-toluene sulfonic acid (144 mg) inchloroform (30 ml) at 0° C. was treated with 3,4-dihydropyran (1.04 ml)dropwise. The reaction mixture was allowed to warm to room temperatureovernight. The reaction mixture was washed with saturated sodiumbicarbonate (40 ml) and water (3×40 ml). The combined aqueous layerswere extracted with dichloromethane (3×60 ml). The organic layers werecombined, dried over magnesium sulfate and concentrated to yield4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid methylester (2.23 g) as a viscous brown oil. LC-MS (Method H): R_(T)=2.79minutes, 278.21 (M+H+ Na)⁺.

(b) 4-Formyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acidethyl ester

By proceeding in a manner similar to Reference Example 54(a) above butusing 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg,Reference Example 57) there was prepared4-formyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethylester (170 mg) was prepared as a viscous yellow oil. LC-MS (Method J):R_(T)=3.29 minutes, 275.30 (M+H+ Na)⁺.

REFERENCE EXAMPLE 55 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester

A stirred suspension of 4-nitro-3-pyrazolecarboxylic acid (1 g) indichloromethane under nitrogen at 0° C. was treated with oxalyl chloride(1.11 ml) followed by dimethylformamide (5 drops). The reaction mixturewas warmed to room temperature and stirred overnight. Methanol (10 ml)was added and the reaction mixture was stirred overnight. The solventwas removed under reduced pressure and azeotroped with toluene twice toyield 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g) as apale green solid. LC-MS (Method H): R_(T)=1.94 minutes, 170.23 (M−H)⁻.

REFERENCE EXAMPLE 56 (a) 1-Methoxy-2-methyl-4-nitrobenzene

2-Methylanisole (2.5 ml) in acetic acid (140 ml) and dichloromethane(150 ml) was cooled to 15° C. Concentrated nitric acid (20 ml) was addedslowly keeping the temperature of the reaction below 40° C. The reactionwas stirred at ambient temperature for 30 minutes and cooled to 0° C.before adding fuming nitric acid (50 ml) dropwise. The reaction mixturewas allowed to warm to ambient temperature slowly and stirred for afurther 4 days. The reaction mixture was poured onto ice water (600 ml)and the organic layer was washed with water (2×40 ml) and saturatedsodium hydrogencarbonate (2×40 ml), dried over magnesium sulfate andconcentrated. The residual deep red solid was subjected to flash silicachromatography on silica eluting with isohexane/ethyl acetate (9:1) to(7:3) to yield 1-methoxy-2-methyl-4-nitrobenzene (2.70 g) as an offwhite solid. LC-MS (Method J): R_(T) 3.74 minutes, 168.27 (M+H)⁺.

(b) 5,6-Dinitro-benzo[1,3]dioxole

By proceeding in a manner similar to Reference Example 56(a) above butusing 1,2-methylenedioxybenzene there was prepared5,6-dinitro-benzo[1,3]dioxole as an orange solid. HPLC (Method C):R_(T)=2.99 minutes; 490.24 (2M+1).

REFERENCE EXAMPLE 57 4-Formyl-1H-pyrazole-3-carboxylic acid ethyl ester

Phosphorus oxychloride (5.07 ml) was added dropwise to dimethylformamide(8.4 ml) at 0° C. under nitrogen. Ethyl pyruvate semicarbazide (4.3 g,Reference Example 58) was added portionwise to the stirring solution at0° C. under a nitrogen positive pressure. The reaction mixture washeated at 60° C. for 2.5 hours and cooled to ambient temperature beforepouring slowly onto ice (30 g). The pH of the reaction mixture wasadjusted to pH12 with 6.25M sodium hydroxide solution whilst maintainingthe temperature at 0° C. The aqueous reaction mixture was heated at 60°C. for 5 minutes and cooled to 0° C. The pH was re-adjusted to pH6 with1M hydrochloric acid. The resulting precipitate which formed after 1hour was collected by filtration to yield4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.02 g) as a paleyellow solid. LC-MS (Method J): R_(T)=2.55 minutes, 169.27 (M+H)⁺,167.30 (M−H)⁻

REFERENCE EXAMPLE 58 Ethyl Pyruvate Semicarbazide

A stirred solution of semicarbazide hydrochloride (11.1 g) and sodiumacetate (8.2 g) in water (250 ml) was treated with ethyl pyruvate (10.9ml) in one portion. The resulting white precipitate was collected byfiltration to yield ethyl pyruvate semicarbazide (16.59 g) as a whitepowder. LC-MS (Method J): R_(T)=2.38 minutes, 174.31 (M+H)⁺, 172.32(M−H)⁻.

REFERENCE EXAMPLE 59 Morpholine-4-carboxylic acid(2,4-dimethoxy-benzyl)-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylmethyl]-amide

A stirred solution of [332 mg, Reference Example 39(b)] in acetic acid(5 ml) was heated at. 120° C. for 5 minutes in a Personal ChemistrySmith Creator microwave. The mixtures from five reactions were combinedand the solvent removed in vacuo to yield morpholine-4-carboxylic acid(2,4-dimethoxy-benzyl)-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-ylmethyl]-amide(1.22 g) as a dark yellow oil. LC-MS (Method J): R_(T)=2.70 minutes,589.63 (M+H)⁺.

REFERENCE EXAMPLE 604-{[(2,4-Dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid ethyl ester

A stirred solution of4-[(2,4-dimethoxy-benzylamino)-methyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid ethyl ester [1 g, Reference Example 54(b)] in tetrahydrofuran (25ml) was treated with 2,4-dimethyoxybenzylamine (0.596 ml). Afterstirring for 12 hours sodium triacetoxyborohydride (1.68 g) was added tothe reaction mixture and the reaction mixture was stirred for a further1 hour before partitioning between ethyl acetate (200 ml) and saturatedsodium hydrogencarbonate (200 ml). The aqueous layer was extracted twicewith ethyl acetate (100 ml) and the combined organic layers were driedover magnesium sulfate and then concentrated in vacuo to yield4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylicacid ethyl ester (1.66 g) as a yellow oil. LC-MS (Method B): R_(T)=2.27minutes, 404.17 (M+H)⁺.

REFERENCE EXAMPLE 61 4-Amino-N-benzyl-3-nitro-benzenesulfonamide

To a stirred suspension of (4-Benzylsulfamoyl-2-nitro-phenyl)-carbamicacid ethyl ester (1.50 g, Reference Example 62) in ethanol (30 ml) wasadded 2M sodium hydroxide solution (5.93 ml) and the reaction heated at75° C. for 2 hours. The reaction mixture was cooled to ambienttemperature, poured onto ice-water and acidified to pH3 with 2Mhydrochloric acid (30 ml). The resultant precipitate was collected byfiltration and dried in vacuo to give4-amino-N-benzyl-3-nitro-benzenesulfonamide (1.01 g) as a yellow solid.LC-MS (METHOD J): R_(T)=3.41 minutes, 308.22 (M+H)⁺.

REFERENCE EXAMPLE 62 (4-Benzylsulfamoyl-2-nitro-phenyl)-carbamic acidethyl ester

To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acidethyl ester (2 g, Reference Example 63) in dichloromethane (50 ml) at 0°C., under a nitrogen atmosphere, was added diisopropylethylamine (2.71ml) and benzylamine (0.850 ml). The reaction was warmed to ambienttemperature and stirred for 12 hours. The reaction mixture was thenwashed with water (2×20 ml) and brine (2×20 ml), dried over magnesiumsulfate, filtered and the filtrate concentrated in vacuo to give thetitle compound (2.29 g) as a brown solid. LC-MS (METHOD J): R_(T)=3.83minutes, 380.12 (M+H)⁺.

REFERENCE EXAMPLE 63 (4-Chlorosulfonyl-2-nitro-phenyl)-carbamic acidethyl ester

To a stirred suspension of (4-chlorosulfonyl-phenyl)-carbamic acid ethylester (5 g, Reference Example 64) in concentrated sulfuric acid (25 ml)at 0° C., was added dropwise a suspension of sodium nitrate (1.61 g) inconcentrated sulfuric acid and the reaction stirred for 3 hours. Thereaction mixture was then poured onto ice, the resultant precipitatecollected by filtration and dried in vacuo to give(4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (4.80 g) asa yellow solid. LC-MS (METHOD B): R_(T)=3.32 minutes, 307.08 (M−H)⁻.

REFERENCE EXAMPLE 64 (4-Chlorosulfonyl-phenyl)-carbamic acid ethyl ester

To a stirred solution of chlorosulfonic acid (20 ml) at 0° C., was addedN-phenylurethane (9.90 g) at such a rate that the temperature did notexceed 20° C. The reaction was then heated at 60° C. for 3 hours, cooledto ambient temperature and poured carefully onto ice. The resultantprecipitate was collected by filtration and dried in vacuo to give(4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (140.50 g) as anoff-white solid. LC-MS (METHOD B): R_(T)=3.11 minutes, 284.23 (M+H)⁺.

REFERENCE EXAMPLE 65 N*1*-Benzyl-4-methanesulfonyl-benzene-1,2-diamine

A stirred solution of benzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine(0.300 g, Reference Example 66) and tin chloride (1.86 g) in ethanol (5ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes.The reaction mixture was basified using saturated sodium hydrogencarbonate solution to pH 8 and extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated to giveN*1*-benzyl-4-methanesulfonyl-benzene-1,2-diamine (0.255 g) as a palebrown solid. LC-MS (METHOD B): R_(T)=2.74 minutes, 275.20 (M−H)⁻.

REFERENCE EXAMPLE 66 Benzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine

To a stirred suspension of (4-fluoro-2-nitrophenyl)methylsulfone (0.50g) and sodium hydrogen carbonate (0.575 g) in ethanol and water (3:2)(30 ml) was added benzylamine (0.374 ml) and the reaction stirred for 16hours. The reaction mixture was then poured onto ice water, theresultant precipitate collected by filtration and dried in vacuo to givebenzyl-(4-methanesulfonyl-2-nitro-phenyl)-amine (0.660 g) as a yellowsolid. LC-MS (METHOD B): R_(T)=2.97 minutes, 307.04 (M+H)⁺.

REFERENCE EXAMPLE 67 4-[2-(3,4-Dinitro-phenoxy)ethyl]-morpholine

A mixture of 3,4-dinitrophenol (250 mg), 4-(2-chloroethyl)morpholinehydrochloride (252 mg) and potassium carbonate (375 mg) indimethylformamide (3 ml) was heated at 120° C. for 20 minutes in aPersonal Chemistry Smith Creator microwave. The reaction mixture waspartitioned between ethyl acetate and water and the organic layer driedover magnesium sulfate, filtered and the filtrate concentrated in vacuoto give 4-[2-(3,4-dinitro-phenoxy)-ethyl-morpholine (319 mg) as a yellowoil. LC-MS (METHOD B): R_(T)=2.13 minutes, 298 (M+H)⁺.

REFERENCE EXAMPLE 68 3-Formyl-1H-indazole-5-carbonitrile

To a suspension of 5-cyanoindole (3.93 g) and sodium nitrite (19.07 g)in water was added 6M hydrochloric acid slowly until the pH was lessthan 2. The suspension was then stirred for 3 hours at ambienttemperature. The mixture was then extracted with ethyl acetate, driedover magnesium sulfate, filtered and the filtrate concentrated in vacuoto give 3-formyl-1H-indazole-5-carbonitrile (4.5 g) as a pale brownsolid. LC-MS (METHOD B): R_(T)=2.47 minutes, 172.29 (M+H)⁺.

In Vitro Test Procedures

A. In Vitro Test Procedures for SYK

1. Inhibitory Effects of Compounds on SYK Kinase

Inhibitory effects of compounds on SYK kinase were determined using atime-resolved fluorescent assay.

The catalytic domain of SYK kinase (residues A340-N635) was expressed asa fusion protein in yeast cells and purified to homogeneity. Kinaseactivity was determined in 50 mM Tris-HCl buffer pH 7.0 containing 50 mMNaCl, 5 mM MgCl₂, 5 mM MnCl₂, 1 μM adenosine triphosphate and 10 μMsynthetic peptide Biotin-(β-Alanine)₃-DEEDYEUPP-NH₂. Enzyme reactionswere terminated by the addition of buffer containing 0.4M KF, 133 mMEDTA, pH 7.0, containing a streptavidin-XL665 conjugate and a monoclonalphosphospecfic antibody conjugated to a europium cryptate (Eu-K).Features of the two fluorophores, XL-665 and Eu-K are given in G. Mathiset al., Anticancer Research, 1997, 17, pages 3011-3014. The specificlong time signal of XL-665, produced only when the synthetic peptide isphosphorylated by SYK, was measured on a Packard Discovery Microplateanalyzer or on an LJL Biosystems Analyst AD microplate reader.Inhibition of SYK activity with compounds of the invention was expressedas percentage inhibition of control activity exhibited in the absence oftest compounds. Particular compounds of the invention inhibit SYKactivity with IC_(50')s in the range 100 micromolar to 0.1 nanomolar.Preferred compounds of the invention inhibit SYK activity with IC_(50')sin the range 5000 nanomolar to 0.1 nanomolar. Particularly preferredcompounds of the invention inhibit SYK activity with IC_(50')s in therange 1000 nanomolar to 0.1 nanomolar. Especially preferred compounds ofthe invention inhibit SYK activity with IC_(50')s in the range 100nanomolar to 0.1 nanomolar. More especially preferred compounds of theinvention inhibit SYK activity with IC_(50')s in the range 10 nanomolarto 0.1 nanomolar.

2. Antigen-Induced Degranulation of Rat Bosophilic Leukemia (RBL) Cellsas Measured by [³H] 5-hydoxytryptamine (Serotonin) Release

2.1 Cell Culture, Labelling of RBL-2H3 Cells and Performance of Assay.

Method A: For each 24-well culture plate to be set up, 6×10⁶ cellsRBL-2H3 cells were washed and resuspended in 15 mL DMEM-10 containing 25μl of 1 mCi/mL [³H]-serotonin (0.5 μCi/mL final concentration) and 1μg/mL (15 mL) of anti-DNP IgE. 0.5 mL of cell suspension was added intoeach well of a 24-well plate. Cells were incubated for 2 days at 37° C.,until they have reached confluence. The medium was gently aspirated fromeach well and the cells were then washed with assay buffer. A finalvolume of 200 mL of assay buffer (+ or − the test compounds at theappropriate concentrations) was then added to each of three replicatewells. 100 ng/mL of DNP (antigen) was then added to all wells (excludingnegative control wells i.e. to measure spontaneous [³H]-serotoninrelease in the absence of receptor cross-linking). The cells wereincubated for 30 minutes at 37° C. and the reaction was stopped bytransferring 100 μl of the supernatant from each sample into a liquidscintillation microtitre plate kept on ice. 200 μl of scintillant-40 wasthen added to each well of the microtitre plate and the plate was readon a Topcount Liquid Scintillation Counter.

Method B: RBL-2H3 cells are maintained in T75 flasks at 37° C. and 5%CO₂, and passaged every 3-4 days. To harvest cells, 5 ml trypsin-EDTA isused to rinse the flask once, then 5 ml trypsin is added to each flask,and incubated at room temperature for 2 minutes. Cells are transferredto a tube with 14 ml medium, spun down at 1100 rpm R_(T) for 5 minutesand resuspended at 2×10⁵/ml. Cells are sensitized by adding 1 μl ofDNP-specific IgE (1 mg/ml stock solution) to every 10 ml of cells. 200μl of cells are added to each well of a flat-bottom 96 well plate(40,000 cells/well), and the plate incubated overnight at 37° C. and 5%CO₂. The next day compounds are prepared in 100% DMSO at 10 mM. Eachcompound is then diluted 1:100 in assay buffer and then diluted furtherin 1% DMSO-assay buffer to obtain final concentrations of 0.03-30 μM. 80μl assay buffer (Hank's Balanced Salt Solution with Ca⁺⁺/Mg⁺⁺, 2 mg/mlglucose, 0.03% BSA) is added to each well, followed by 10 μl of dilutedcompound. Incubation follows for 5 minutes. 10 μl of DNP-HSA (100 ng/ml)is added to each well and incubated at 37° C. (no CO₂) for 30 minutes.As one control, 1% DMSO alone (no compound) is added to a set of wellsto determine total release. As another control, buffer is added insteadof DNP-HSA to another set of wells to determine the assay background.After 30 minutes incubation, the supernatants are transferred to a new96-well plate. Add 50 μl supernatant to each well of an assay plate. Add100 μl of substrate solution (5 mM PNAG in 0.4M citric acid, 0.2MNa₂HPO₄) to each well and incubate at 37° C. for 90 minutes. Add 50 μlof 0.4 M glycine solution to stop the reaction and the plate is read at405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculation of Results

Method A

-   (i) The mean±s.e.m. of each set of triplicate wells was calculated.-   (ii) Maximum response was the positive control wells containing    antigen (10 ng/mL) but no compound.-   (iii) Minimum response was the control wells containing no antigen    and no compound.-   (iv) Using these values as the maximum (100%) and minimum (0%)    values respectively, the data was normalised to give a percentage of    the maximum response.-   (v) A dose response curve was plotted and the IC₅₀ of the compound    was calculated.    Method B-   (i) The mean±SD of each set of triplicate wells was calculated.-   (ii) Maximum response was the positive control wells containing    antigen (100 ng/mL) but no compound.-   (iii) Minimum response was the control wells containing buffer (no    antigen) and no compound.-   (iv) Using these values as the maximum (100%) and minimum (0%)    values respectively, the experimental data was calculated to yield a    percentage of the maximum response (designated % control).-   (v) A dose response curve was plotted and the IC₅₀ of the compound    was calculated using Prism GraphPad software and nonlinear least    squares regression analysis.    B. In Vitro Test Procedures for KDR    1. Inhibitory Effects of Compounds on KDR

The inhibitory effect of the compounds is determined in a test ofphosphorylation of a substrate by the enzyme KDR in vitro by theflasplate technique (96-well plate, NEN).

The cytoplasmic domain of human KDR enzyme is cloned in the form of aGST fusion into the baculovirus expression vector pFastBac. The proteinis expressed in the SF21 cells and purified to about 60% homogeneity.

The kinase activity of KDR is measured in 20 mM MOPS, 10 mM MgCl2, 10 mMMnCl2, 1 mM DTT, 2.5 mM EGTA, 10 mM β^(˜)glycerophosphate, pH 7.2 in thepresence of 10 mM MgCl2, 100 μM Na3VO4, 1 mM NaF. 10 μl of the compoundare added to 70 μl of kinase buffer containing 100 ng of KDR enzyme at4° C. The reaction is initiated by adding 20 μl of solution containing 2μg of substrate (fragment SH2-SH3 of PLCγ expressed in the form of a GSTfusion protein), 2 μCi γ33P[ATP] and 2 μM cold ATP. After incubating for1 hour at 37° C., the reaction is quenched by adding 1 volume (100 μl)of 200 mM EDTA. The incubation buffer is removed and the wells arewashed three times with 300 μl of PBS. The radioactivity is measured ineach well using a Top Count NXT instrument (Packard).

Background noise is determined by measuring the radioactivity in wellsin quadruplet containing radioactive ATP and the substrate alone.

An activity control is measured in wells in quadruplet containing allthe reagents (γ33P-[ATP], KDR and the substrate PLCγ) and in the absenceof compound.

The inhibition of the KDR activity with the compound of the invention isexpressed as a percentage of inhibition of the control activitydetermined in the absence of compound.

The compound SU5614 (Calbiochem) (1 μM) is included in each plate asinhibition control.

The IC₅₀ values for the compounds are calculated by plotting thedose-response curves. The IC₅₀ corresponds to the concentration ofcompound that induces a 50% inhibition of the kinase activity.Particular compounds of the invention inhibit KDR activity withIC_(50')s in the range 100 micromolar to 10 nanomolar. Preferredcompounds of the invention inhibit KDR activity with IC_(50')s in therange 3000 nanomolar to 10 nanomolar. Particular preferred compounds ofthe invention inhibit KDR activity with IC_(50')s in the range 300nanomolar to 10 nanomolar.

II) Cellular Activity on Endothelial Cells

1) Inhibition of the VEGF-Dependent Proliferation of HDMECs

The anti-KDR activity of the molecules is assessed by incorporating[14C]-thymidine into HDMECs (Human Dermal Microvascular EndothelialCells) in response to VEGF.

HDMECs (Promocell, passage 5 to 7) are inoculated in 100 μl at 5000cells per well in Cytostar (Amersham) 96-well plates precoated withattachment factor (AF, Cascad Biologics) at 37° C., 5% CO₂, on day 1. Onday 2, the complete medium (basal medium supplemented with 5% FCS and amixture of growth factors) is replaced with minimum medium (basal mediumsupplemented with 5% FCS) and the cells are incubated for 24 hours. Onday 3, the medium is replaced with 200 μl of fresh medium that has orhas not been supplemented with 100 ng/ml of VEGF (R&D System) andcontaining or not containing the compound of the invention and 0.1 μCi[14C]-thymidine. The cells are incubated at 37° C. under 5% CO₂ for 4days. The incorporation of [14C]-thymidine is then quantified bycounting the radioactivity. The tests are performed in 3 wells. Thefinal concentration of DMSO in the test is 0.1%. The % of inhibition iscalculated as follows: [cpm(+VEGF)−cpm (+VEGF+cpd)/cpm(+VEGF)−cpm (BM5%FCS)]×100.

2) Inhibition of the Production of TF (Tissue Factor) by EndothelialCells in Response to VEGF

The endothelial cells are inoculated at 20 000 cells per well in a96-well plate precoated with attachment factor. After culturing for 8hours, the medium is changed and the cells are preincubated with thecompounds (0.1% DMSO final) in basal medium for 16 hours. The synthesisof the TF (tissue factor) is induced by adding VEGF (100 ng/ml final).After incubating for 6 hours, the cells are rinsed and lysed. The tissuefactor is then detected by means of the Imubind ELISA test.

3) Effect of the Molecules on the VEGF-Independent Growth of HDMECs

The HDMECs (5000 cells per well) are inoculated in complete medium inCytostar (Amersham) 96-well plates precoated with attachment factor (AF,Cascad Biologics) at 37° C., 5% CO₂, on day 1. The whole medium is thenremoved and the cells are incubated in 200 μl of complete mediumcontaining the molecules of the invention and [14C]-thymidine (0.1 μCi).The incorporation of the [14C]-thymidine is measured using a Wallaccounter after incubating for 3 days. The % of inhibition is calculatedas follows: [cpm(CM)−cpm (CM+cpd)/cpm(CM)]×100.

Table 5 below gives the results obtained in the above tests for theproducts indicated as examples in the present patent application. TABLE5 IC₅₀ (μM) on % of inhibition of the inhibition of the phosphorylationof PLCγ by Example phosphorylation of KDR (product tested at a No. PLCγby KDR concentration of 10 μM) 14 1.2 15 0.8 16 2 20 3.4 21 — 35 1 0.472 0.45 3 — 91.8 4 0.45 5 — 91.9 6 0.33 7 0.72 8 0.67 9 0.35 10 0.34 110.26 12 0.16 13 0.61 18 — 91.2 23 2

The pharmacological results obtained in the above tests for productsindicated in examples in the present application are given in the table6 below, the degrees of activities of the products being indicated by +signs according to the ranges of activity indicated in the table, i.e.:

+ for an activity of greater than 3 micromolar

-   -   -   ++ for an activity of between 0.3 and 3 micromolar

+++ for an activity of less than 0.3 micromolar TABLE 6 Activity +:IC₅₀ > 3 μM Example Molecular ++: 0.3 μM < IC₅₀ < 3 μM No. Molecularformula weight +++: IC₅₀ < 0.3 μM 28 C22H18N6O3S 446.49 +++ 29C20H21N5O2 363.42 ++ 30 C22H16BrN5O 446.31 +++ 31 C23H19N5O3S 445.50 +++32 C26H19N5O 417.47 ++ 33 C23H16F3N5O 435.41 ++ 34 C20H15N5OS 373.44 ++35 C24H22N6O 410.48 ++ 36 C26H30N6O3 474.56 ++ 37 C22H16N6O3 412.41 +++38 C21H16N6O 368.40 ++ 39 C22H16BrN5O 446.31 ++ 40 C23H19N5O2 397.44 ++41 C23H17N5O3 411.42 ++ 42 C24H17N5OS 423.50 ++ 43 C21H19N7O 385.43 ++44 C23H16F3N5O2 451.41 ++ 45 C23H19N5O 381.44 +++ 46 C21H17N5OS 387.46++ 47 C23H16F3N5O 435.41 ++ 48 C28H21N5O2 459.51 ++ 49 C23H16F3N5O2451.41 ++ 50 C21H23N5O2 377.45 ++ 51 C20H17N7O 371.40 ++ 52 C25H23N5O409.49 ++ 53 C22H19N5O2 385.43 ++ 54 C24H17N5OS 423.50 ++ 55 C26H24N6O3468.52 ++ 56 C21H15C1N6O 402.84 +++ 57 C24H17N5OS2 455.56 ++ 58C24H19N5O2 409.45 +++ 59 C23H16N6O 392.42 ++ 60 C24H16C1N5OS 457.94 + 61C23H16F3N5O 435.41 + 62 C23H19N5OS 413.50 +++ 63 C24H17N5OS 423.50 +++64 C21H21N5O2 375.43 ++ 65 C24H19N5O3 425.45 ++ 66 C20H15N5O2 357.37 ++67 C22H16N6O3 412.41 ++ 68 C20H15N5OS 373.44 ++ 69 C24H21N5O 395.47 ++70 C24H19N7O 421.46 ++ 71 C23H19N5O 381.44 +++ 72 C22H16C1N5O 401.86 +++73 C22H18N6O3S 446.49 ++ 74 C20H21N5O2 363.42 + 75 C22H16BrN5O 446.31 +76 C26H19N5O 417.47 + 77 C20H15N5OS 373.44 + 78 C24H22N6O 410.48 + 79C22H16N6O3 412.41 + 80 C21H16N6O 368.40 ++ 81 C22H16BrN5O 446.31 + 82C23H19N5O2 397.44 ++ 83 C24H17N5OS 423.50 + 84 C28H21N5O2 459.51 + 85C23H16F3N5O2 451.41 + 86 C21H15C1N6O 402.84 + 87 C24H19N5O2 409.45 + 88C23H16F3N5O 435.41 + 89 C23H19N5OS 413.50 +++ 90 C20H15N5O2 357.37 ++ 91C22H16N6O3 412.41 ++ 92 C24H21N5O 395.47 ++ 93 C22H16C1N5O 401.86 + 94C21H15N5O 353.38 ++ 95 C22H17N5O 367.41 + 96 C23H19N5O 381.44 + 97C20H14N4 310.36 + 98 C20H12C12N4 379.25 + 99 C24H16N4 360.42 + 100C20H13FN4 328.35 ++ 101 C20H13C1N4 344.80 + 102 C21H16N4O 340.39 ++ 103C20H12C1FN4 362.79 ++ 104 C20H12C12N4 379.25 + 105 C26H16N4S2 448.57 +106 C26H18N4 386.46 + 107 C21H16N4 324.39 + 108 C21H16N4 324.39 ++ 109C21H16N4 324.39 ++ 110 C18H12N4S 316.39 ++ 111 C21H13F3N4 378.36 + 112C21H13F3N4 378.36 + 113 C20H13C1N4 344.80 ++ 114 C21H16N4O 340.39 ++ 115C22H18N4 338.41 ++ 116 C22H18N4 338.41 + 117 C21H14N4O2 354.37 ++ 118C24H22N4 366.47 + 119 C20H20N4 316.41 ++ 120 C22H18N4O2 370.41 ++ 121C20H14N4O 326.36 ++ 122 C20H14N4O 326.36 ++ 123 C20H12C12N4 379.25 + 124C21H13F3N4O 394.36 + 125 C22H16N4O 352.40 + 126 C22H14N4S 366.45 + 127C23H20N4O3 400.44 ++ 128 C20H14N4OS 358.42 ++ 129 C22H16N4O 352.40 + 130C27H20N4O 416.48 + 131 C26H17FN4 404.45 + 132 C22H14N4S 366.45 + 133C21H16N4O 340.39 ++ 134 C22H18N4S 370.48 + 135 C20H12F2N4 346.34 ++ 136C21H13F3N4O 394.36 + 137 C21H15FN4 342.38 ++ 138 C22H15FN4 354.39 + 139C22H15C1N4 370.84 + 140 C23H18N4O2 382.42 + 141 C21H16N4O 340.39 ++ 142C18H12N4O 300.32 ++ 143 C27H20N4O 416.48 + 144 C23H20N4 352.44 ++ 145C21H16N4O2S 388.45 + 146 ++ 147 ++ 148 ++ 149 ++ 150 ++ 151 ++ 152 ++153 ++ 154 ++ 155 ++ 156 ++ 157 +++ 158 ++ 159 ++ 160 ++ 161 ++ 162 +163 + 164 + 165 + 166 ++ 167 +++ 168 +++ 169 +++ 170 ++ 171 ++ 172 ++173 ++ 174 ++ 175 ++ 176 +++ 177 +++ 178 +++ 179 +++ 180 +++ 181 ++ 182++ 183 + 184 ++ 185 ++ 186 + 187 + 188 ++ 189 + 190 + 191 ++ 192 + 193++ 194 + 195 + 196 + 197 ++ 198 + 199 + 200 + 201 + 202 + 203 + 204 +205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 + 213 + 214 ++ 215 + 216 +217 ++ 218 + 219 + 220 + 221 + 222 + 223 + 224 ++ 225 + 226 + 227 + 228+C. In Vitro Test Procedures for ITK1. Inhibitory Effects of Compounds on ITK Kinase

Inhibitory effects of compounds on ITK kinase were determined using aFluorescence Polarization assay.

ITK kinase was produced with Baculovirus expression system.

1.1 Assay Technology

The assay measures the autophosphorylation of the ITK kinase. The assayis configured based on Fluorescence Polarization method. The enzyme isincubated with ATP and compound. After incubation, a mixture containingfluorescence labeled phospho-peptide tracer and anti-phospho-tyrosineantibody (CoreHTS tyrosine kinase assay kit, P2837, Panvera) is added inorder to generate the specific signal that is reversely proportional tothe phosphorylation of the enzyme. The phosphorylated ITK generated fromthe kinase reaction will compete specifically for the antibody andrelease the fluorescence labeled tracer. Inhibition of ITK kinaseactivity will result in increased FP value.

1.2 Assay Conditions

The assay is run in BD black 384-shallow well plate. For enzymereaction, the final reagent concentration/well: 16.5 nM ITK enzyme, 50CMATP, 20 mM Hepes (pH 7.5), 0.15M NaCl, 3 mM MgCl₂, 1 mM MnCl₂, 0.01%Triton X-100, 1 mM DTT, 5% glycerol and 0.1% γ-globulin. Incubationtime: 45 minutes. Temperature: 25° C. Reaction volume: 10 μL. Forimmuno-reaction, add 10 μL of Stop-Detection mixture containing 10 mMEDTA, 1:2 dilution of antibody and 1:4 dilution of tracer in 1× dilutionbuffer (Panvera). Incubation time: 90 minutes at 37° C. followed by roomtemperature 60 minutes.

1.3 Assay Procedure:

-   1. Add 5.0 μL ATP solution to each well of the black 384-shallow    well plate.-   2. Add 1.0 μL compounds or 1% DMSO in TBS buffer.-   3. Start Reaction by adding 5.0 μL enzyme solution.-   4. Incubate at 25° C. for 45 minutes.-   5. Add 10 μL of stop-detection solution.-   6. Incubate for 90 minutes at 37° C. followed by incubation at room    temperature for 60 minutes.-   7. Read by LJL Acquest at FP mode using a fluorescence filter set    (E_(x)=485 nm, E_(m)=535 nm) with FL dichroic mirror. Integration    Time: 200,000 μs. G factor instrument dependent    $\left\lbrack {{G\quad{factor}} = \frac{\left( {S_{TracerOnly} - S_{Buffer}} \right)}{\left( {S_{TracerOnly} - S_{Buffer}} \right)}} \right\rbrack$

Inhibition of ITK activity with compounds of the invention was expressedas percentage inhibition of control activity determined in the absenceof test compounds.

The IC₅₀ values for the compounds are calculated by plotting thedose-response curves. The IC₅₀ corresponds to the concentration ofcompound that induces a 50% inhibition of the kinase activity.Particular compounds of the invention inhibit ITK activity withIC_(50')s in the range 100 micromolar to 1 micromolar.

In Vivo Test Procedures

A. In Vivo Test Procedures for SYK

1. Inhibition of Antigen-Dependent Passive Cutaneous Anaphylaxis.

Compounds of the invention were assessed in the Balb/c mouse passivecutaneous anaphylaxis (PCA) model. The model used in these in vivostudies mimics relevant features of mast cell-driven antigen-dependentactivation and functional responses. These studies demonstrated thatcompounds of the invention inhibit the increase in edema observed in thesensitized mouse ear following antigen exposure.

Protocol for Sensitization and Challenge

Balb/c mice were sensitized in the right ear on day 0 with monoclonalanti-DNP IgE (25 μg) administered intradermally in the ear pinnae. Theleft ear was injected with PBS to serve as a control. Sixteen to twentyhours after sensitization, mice were antigen challenged with 150 μgDNP-albumin administered i.v.

Protocol for Dosing and Calculation of Results

Test drug was administered orally 15-60 minutes before DNP-albuminantigen challenge. Doses of compound were administered at half logdivisions between 3 and 100 mg/kg. A control set of mice wasadministered vehicle alone, and thereafter treated identically. Earthickness was measured at t=0, 15, 30 or 60 minutes after DNP-albuminantigen challenge, in both ears, by digital calipers and expressed inunits of mm×0.01. Ear thickness at t=0 was recorded to serve as abaseline. The net increase in both the right and left ear was calculatedby subtracting the values at t=0 from those at t=15, 30 or 60 minutes.Percent inhibition of ear edema was then calculated as [ear thickness ofcontrol-(ear thickness of right ear-ear thickness of left ear)]/earthickness of control×100 for each time point measured.

Results

(i) The compound demonstrated dose-dependent inhibition of ear edemafollowing oral administration of 3-100 mg/kg. Inhibition of ear edemawas observed at t=15, 30 and 60 minutes after antigen challenge.

These results indicate that compounds of the invention inhibit mast cellactivation and functional responses when given orally in a mouse modelof passive cutaneous anaphylaxis.

2. Antigen-Induced Degranulation of Rat Bosophilic Leukemia (RBL) Cellsas Measured by [³H] 5-hydoxytryptamine (Serotonin) Release

2.1 Cell Culture, Labelling of RBL-2H3 Cells and Performance of Assay.

Method A: For each 24-well culture plate to be set up, 6×10⁶ cellsRBL-2H3 cells were washed and resuspended in 15 mL DMEM-10 containing 25μl of 1 mCi/mL [³H]-serotonin (0.5 μCi/mL final concentration) and 1μg/mL (15 mL) of anti-DNP IgE. 0.5 mL of cell suspension was added intoeach well of a 24-well plate. Cells were incubated for 2 days at 37° C.,until they have reached confluence. The medium was gently aspirated fromeach well and the cells were then washed with assay buffer. A finalvolume of 200 mL of assay buffer (+ or − the test compounds at theappropriate concentrations) was then added to each of three replicatewells. 100 ng/mL of DNP (antigen) was then added to all wells (excludingnegative control wells i.e. to measure spontaneous [³H]-serotoninrelease in the absence of receptor cross-linking). The cells wereincubated for 30 minutes at 37° C. and the reaction was stopped bytransferring 100 μl of the supernatant from each sample into a liquidscintillation microtitre plate kept on ice. 200 μl of scintillant-40 wasthen added to each well of the microtitre plate and the plate was readon a Topcount Liquid Scintillation Counter.

Method B: RBL-2H3 cells are maintained in T75 flasks at 37° C. and 5%CO₂, and passaged every 3-4 days. To harvest cells, 5 ml trypsin-EDTA isused to rinse the flask once, then 5 ml trypsin is added to each flask,and incubated at room temperature for 2 minutes. Cells are transferredto a tube with 14 ml medium, spun down at 1100 rpm R_(T) for 5 minutesand resuspended at 2×10⁵/ml. Cells are sensitized by adding 1 μl ofDNP-specific IgE (1 mg/ml stock solution) to every 10 ml of cells. 200μl of cells are added to each well of a flat-bottom 96 well plate(40,000 cells/well), and the plate incubated overnight at 37° C. and 5%CO₂. The next day compounds are prepared in 100% DMSO at 10 mM. Eachcompound is then diluted 1:100 in assay buffer and then diluted furtherin 1% DMSO-assay buffer to obtain final concentrations of 0.03-30CM. 80μl assay buffer (Hank's Balanced Salt Solution with Ca⁺⁺/Mg⁺⁺, 2 mg/mlglucose, 0.03% BSA) is added to each well, followed by 10 μl of dilutedcompound. Incubation follows for 5 minutes. 10 μl of DNP-HSA (100 ng/ml)is added to each well and incubated at 37° C. (no CO₂) for 30 minutes.As one control, 1% DMSO alone (no compound) is added to a set of wellsto determine total release. As another control, buffer is added insteadof DNP-HSA to another set of wells to determine the assay background.After 30 minutes incubation, the supernatants are transferred to a new96-well plate. Add 50 μl supernatant to each well of an assay plate. Add100 μl of substrate solution (5 mM PNAG in 0.4M citric acid, 0.2MNa₂HPO₄) to each well and incubate at 37° C. for 90 minutes. Add 50 μlof 0.4 M glycine solution to stop the reaction and the plate is read at405 nm on a Molecular Devices SpectraMax 250 plate reader.

2.2 Calculation of Results

Method A

-   (i) The mean±s.e.m. of each set of triplicate wells was calculated.-   (ii) Maximum response was the positive control wells containing    antigen (10 ng/mL) but no compound.-   (iii) Minimum response was the control wells containing no antigen    and no compound.-   (iv) Using these values as the maximum (100%) and minimum (0%)    values respectively, the data was normalised to give a percentage of    the maximum response.-   (v) A dose response curve was plotted and the IC₅₀ of the compound    was calculated.    Method B-   (i) The mean±SD of each set of triplicate wells was calculated.-   (ii) Maximum response was the positive control wells containing    antigen (100 ng/mL) but no compound.-   (iii) Minimum response was the control wells containing buffer (no    antigen) and no compound.-   (iv) Using these values as the maximum (100%) and minimum (0%)    values respectively, the experimental data was calculated to yield a    percentage of the maximum response (designated % control).-   (v) A dose response curve was plotted and the IC₅₀ of the compound    was calculated using Prism GraphPad software and nonlinear least    squares regression analysis.

1. A pharmaceutical composition comprising a compound of general formula (Ix)

wherein X represents C—R² and W, Y and Z, which may be identical or different, represent CH or CR³; or W represents CH, X represents N, Y represents CH or CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents CH and CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents N, and Z is CH or CR³; or W represents N, X represents CH or CR², Y represents CH or CR³, and Z represents N; or W represents N, X represents N, Y represents CH or CR³, and Z represents CH or CR³; A₅ represents H or alkyl; R¹ represents aryl or heteroaryl, each optionally substituted by one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² and —S(O)_(n)OR⁴; R² and R³ are such that: R² and R³, which may be identical or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴; or R² represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY 1Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴ and R³ represents alkyl, haloalkyl, halogen and OR⁶; or R² and R³ groups on adjacent carbon atoms may form a 5- to 6-membered carbon-based ring containing one or more heteroatoms, which may be identical or different, chosen from O, N and S, and which may be optionally substituted by alkyl; R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, —C(═O)NY³Y⁴, —C(═O)OR⁶, —N(R⁶)C(═O)NY¹Y², —NY¹Y², —OR⁵ or alkyl substituted by —NY³Y⁴; R⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R⁶ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; n is zero or an integer 1 or 2; Y¹ and Y² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted by one or more groups selected from cyano, aryl, heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY³Y⁴, —NY³Y⁴ and —OR⁵, or the group —NY¹Y² may form a cyclic amine; Y³ and Y⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY³Y⁴ may form a cyclic amine; where all the alkyl, alk, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—COalk), —C(═O)OR⁶, —C(═O)R⁶, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴ and NY³Y⁴ radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH—C(O)R⁵; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate; together with one or more pharmaceutically acceptable carriers or excipients.
 2. A compound of general formula (Ix)

wherein X represents C—R² and W, Y and Z, which may be identical or different, represent CH or CR³; or W represents CH, X represents N, Y represents CH or CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents CH and CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents N, and Z is CH or CR³; or W represents N, X represents CH or CR², Y represents CH or CR³, and Z represents N; or W represents N, X represents N, Y represents CH or CR³, and Z represents CH or CR³; A₅ represents H or alkyl; R¹ represents aryl or heteroaryl, each optionally substituted by one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² and —S(O)_(n)OR⁴; R² and R³ are such that: R² and R³, which may be identical or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴; or R² represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴ and R³ represents alkyl, haloalklyl, halogen and OR⁶; or R² and R³ groups on adjacent carbon atoms may form a 5- to 6-membered carbon-based ring containing one or more heteroatoms, which may be identical or different, chosen from O, N and S, and which may be optionally substituted by alkyl; R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, —C(═O)NY³Y⁴, —C(═O)OR⁶, —N(R⁶)C(═O)NY¹Y², —NY¹Y², —OR⁵ or alkyl substituted by —NY³Y⁴; R⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R⁶ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; n is zero or an integer 1 or 2; Y¹ and Y² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted by one or more groups selected from cyano, aryl, heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY³Y⁴, —NY³Y⁴ and —OR⁵, or the group —NY¹Y² may form a cyclic amine; Y³ and Y⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY³Y⁴ may form a cyclic amine; where all the alkyl, alk, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—COalk), —C(═O)OR⁶, —C(═O)R⁶, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴ and NY³Y⁴ radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH—C(O)R⁵; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 3. A compound of formula (Ix)

wherein X represents C—R² and W, Y and Z, which may be identical or different, represent CH or CR³; or W represents CH, X represents N, Y represents CH or CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents CH and CR³, and Z represents CH or CR³; or W represents N, X represents CH or CR², Y represents N, and Z is CH or CR³; or W represents N, X represents CH or CR², Y represents CH or CR³, and Z represents N; or W represents N, X represents N, Y represents CH or CR³, and Z represents CH or CR³; A₅ represents H or alkyl; R¹ is a pyrazolyl moiety

in which R⁷ is hydrogen or alkyl, and R⁸ and R⁹ are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y²; or R⁸ and R⁹ together with the carbon atoms to which they are attached form (i) a 5 to 8 membered carbocyclic ring optionally substituted by one or more carbocyclic ring substituents; (ii) a phenyl ring optionally substituted by one or more aryl group substituents; (iii) a 5 or 6 membered heteroaromatic ring in which one or more of the ring members is/are nitrogen, oxygen or sulfur and which is optionally substituted by one or more groups selected from haloalkyl, hydroxy, halo, cyano, nitro, R⁴, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)SO₂R⁴, —NY¹Y² and —OR⁵; or (iv) a 5 or 6 membered heterocyclic ring optionally substituted by alkyl or oxo, and containing a heteroatom-containing group selected from O, S, SO₂, and NY⁵, where Y⁵ is hydrogen, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴; R² and R³ are such that: R² and R³, which may be identical or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴; or R² represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴, —S(O)_(n)NY¹Y² or —S(O)_(n)OR⁴ and R³ represents alkyl, haloalkyl, halogen and OR⁶; or R² and R³ groups on adjacent carbon atoms may form a 5- to 6-membered carbon-based ring containing one or more heteroatoms, which may be identical or different, chosen from O, N and S, and which may be optionally substituted by alkyl; R⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, —C(═O)NY³Y⁴, —C(═O)OR⁶, —N(R⁶)C(═O)NY¹Y², —NY¹Y², —OR⁵ or alkyl substituted by —NY³Y⁴; R⁵ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R⁶ is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; n is zero or an integer 1 or 2; Y¹ and Y² are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted by one or more groups selected from cyano, aryl, heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY³Y⁴, —NY³Y⁴ and —OR⁵, or the group —NY¹Y² may form a cyclic amine; Y³ and Y⁴ are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group —NY³Y⁴ may form a cyclic amine; where all the alkyl, alk, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—COalk), —C(═O)OR⁶, —C(═O)R⁶, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴ and NY³Y⁴ radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH—C(O)R⁵; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate; provided that the compound is other than 2-(2H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-methyl-2H-pyrazol-3-yl)-1H-benzoimidazole; 5-methyl-6-[2-(2H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6-[2-(2H-pyrazol-3-yl)-1H-benzoimidazol-4-yl]4,5-dihydro-2H-pyridazin-3-one; 3,5-bis(benzimidazol-2-yl)-1H-pyrazole; 5,6-dimethyl-2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-methyl-2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dichloro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 5-nitro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole-5-carboxylic acid; 2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 5,6-dimethyl-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 5-methyl-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 6-chloro-2-(5-methyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 5-chloro-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole; 5,6-dichloro-2-(5-phenyl-1H-pyrazole-3-yl)-1H-benzoimidazole; N-[2-(5-isoquinolin-4-yl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-methanesulfonamide; 3-(1H-benzoimidazol-2-yl)-5-(1H-indazol-4-yl)-1H-indazole, 3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-2-methoxyphenol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-5-yl]isoquinoline; 4-{3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-isoquinoline; 4-[3-(4-chloro-1H-benzoimidazol-2-yl)-1H-indazol-5-yl]-isoquinoline; 4-[2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-phenol; 3-[5-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole; 3-[5-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole; 3-[5-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-1H-indazole; 3-(1H-benzoimidazol-2-yl)-5-phenyl-1H-indazole; 2-(4-bromo-1-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-tert-butyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-phenyl)-1H-indazole; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid; 5-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-2-hydroxy-benzoic acid methyl ester; 5-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-furan-2-carboxylic acid methyl ester; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (3-hydroxy-4-methoxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (5-hydroxy-1H-pyrazol-3-yl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (1H-pyrazol-3-yl)-amide; [3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (9H-purin-6-yl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid dimethylamide; [3-(1H)-benzoimidazol-2-yl)-1H-indazol-6-yl]-morpholin-4-yl-methanone; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid pyrazin-2-ylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid cyclohexylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (1H-indazol-5-yl)-amide; [3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-pyrrolidin-1-yl-methanone; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (1H-indazol-5-yl)-amide; [3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-[4-(furan-2-carbonyl)-piperazin-1-yl]-methanone; [3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-(4-methyl-piperazin-1-yl)-methanone; 1-{4-[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-piperazin-1-yl}-ethanone; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (6-methoxy-pyridin-3-yl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (3-hydroxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid pyridin-4-ylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (2-hydroxy-ethyl)-methyl-amide; 3-{[3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carbonyl]-amino}-butyric acid ethyl ester; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (3-hydroxy-propyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid phenylamide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid pyridin-3-ylamide; 3-(6-methoxy-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-6-pyridin-4-yl-1H-indazole; 3-(5-chloro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(5-fluoro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(6-tert-butyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(5,6-difluoro-1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-2,3-dimethyl-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-2-methyl-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (4-hydroxy-phenyl)-amide; 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid cyclopropylamide; 2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-sulfonic acid amide; 4-[3-(6-dimethylamino-1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol; 2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-carboxylic acid methylamide; 3-methoxy-4-{3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-6-yl}-phenol; 2-[6-(4-hydroxy-2-methoxy-phenyl)-1H-indazol-3-yl]-3H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 4-[3-(1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol; 3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol; 3-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-phenol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3,5-dimethyl-phenol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-phenoxy-phenol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-benzene-1,3-diol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-3-methoxy-phenol; 4-[3-(1H-benzoimidazol-2-yl)-1H-indazol-6-yl]-2-methoxy-phenol; N-{3-[3-(1H-benzoimidazol-2-yl-1H-indazole-6-carbonyl]-phenyl}-benzamide; 6-[2-(1,5-dimethyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6-[2-(1-methyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5-yl]-4,5-dihydro-2H-pyridazin-3-one; 8-(1,5-dimethyl-1H-pyrazol-3-yl)-7H-purine; 2-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridine or 2-(5-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-b]pyridine.
 4. A compound according to claim 2 wherein R¹ is optionally substituted heteroaryl.
 5. A compound according to claim 4 wherein R¹ is optionally substituted dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyridazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl, thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, tetrahydroindazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl.
 6. A compound according to claim 4 heteroaryl is optionally substituted by one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y².
 7. A compound according to claim 5 wherein dihydrofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyridazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyrazolyl, pyrazolyl, thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, tetrahydroindazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl is optionally substituted by one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y².
 8. A compound according to claim 2 wherein R¹ is

where R⁷ is hydrogen or alkyl, and R⁸ and R⁹ are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y²; or R⁸ and R⁹ together with the carbon atoms to which they are attached form (i) a 5 to 8 membered carbocyclic ring optionally substituted by one or more carbocyclic ring substituents; (ii) a phenyl ring optionally substituted by one or more aryl group substituents; (iii) a 5 or 6 membered heteroaromatic ring in which one or more of the ring members is/are nitrogen, oxygen or sulfur and which is optionally substituted by one or more groups selected from haloalkyl, hydroxy, halo, cyano, nitro, R⁴, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)S₂R⁴, —NY¹Y² and —OR⁵; or (iv) a 5 or 6 membered heterocyclic ring optionally substituted by alkyl or oxo, and containing a heteroatom-containing group selected from O, S, SO₂, and NY⁵, where Y⁵ is hydrogen, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or —SO₂R⁴.
 9. A compound according to claim 2 wherein W is CH; X is CR²; Y is CH or CR³; and Z is CH or CR³.
 10. A compound according to any one of claim 2 wherein W is CH; when X is N; Y is CH or CR³; and Z is CH or CR³.
 11. A compound according to any one of claim 2 wherein W is N; X is CH or CR²; Y is CH or CR³; and Z is CH or CR³.
 12. A compound according to any one of claim 2 wherein W is N; X is CH or CR²; Y is CH or CR³; and Z is N.
 13. A compound according to claim 2 of formula (Ixa)

wherein R⁷ is hydrogen or alkyl; R⁸ and R⁹ are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —NY¹Y², —OR⁴, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ and —S(O)₂NY¹Y²; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 14. A compound according to claim 13 wherein W is CH; X is CH, Y is CH; and Z is CH or C—CH₃.
 15. A compound according to claim 13 wherein W represents CH; X represents CH; Z represents CH; and Y represents C—C₁₋₄alkyl; C-aryl; C—CN; C—NO₂; C-halo; C-haloalkyl; C-heteroaryl; C—OR⁴; C—C(═O)R⁴; C—C═O)NY¹Y²; C—C(═O)OR⁴; C—NHC(═O)R⁴; C—CH(OH)aryl; C—S(O)₂NY¹Y²; or C—S(O)_(n)R⁴.
 16. A compound according to claim 13 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and Z represents CH.
 17. A compound according to claim 13 wherein W represents CH; X represents CH; Y represents C—CH₃; and Z represents C—CH₃.
 18. A compound according to claim 13 wherein W represents CH; X represents CR²; and Y represents CR³, where R² and R³ form the group —CH₂—O—CH₂; and Z represents CH.
 19. A compound according to claim 13 wherein W represents CH; X represents CR²; Y represents CR³, where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 20. A compound according to claim 13 wherein R⁷ represents hydrogen.
 21. A compound according to claim 13 wherein R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y² or —OR⁵.
 22. A compound according to claim 13 wherein R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, where R⁴ is alkyl optionally substituted by aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or where R⁴ is NY¹Y² or —OR⁵, or where R⁴ is aryl, or where R⁴ is cycloalkyl, or where R⁴ is heteroaryl, or where R⁴ is heterocycloalkyl; or R⁹ represents —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 23. A compound according to claim 13 wherein W represents CH; X represents CH; Y represents CH; Z represents CH or C—CH₃; R⁷ represents hydrogen; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y²; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, particularly —NHC(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 24. A compound according to claim 13 wherein W represents CH; X represents CH; Z represents CH; Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C-heteroaryl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², C—C(═O)OR⁴, or C—CH(OH)aryl; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y² or —OR⁵; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 25. A compound according to claim 13 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y², or —OR⁵; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 26. A compound according to claim 13 wherein W represents CH; X represents CH; Y represents C—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y², or —OR⁵; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y²; —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 27. A compound according to claim 13 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z represents CH; R⁷ represents hydrogen; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y², or —OR⁵; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y²; —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y², or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 28. A compound according to claim 13 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Z represents CH; R⁷ represents hydrogen; R⁸ represents hydrogen, C₁₋₄alkyl, —SR⁴, —NY¹Y², or —OR⁵; and R⁹ represents hydrogen, C₁₋₇alkyl, aryl, —C(═O)NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —NY¹Y² or alkyl substituted by —N(R⁶)C(═O)NY¹Y².
 29. A compound according to claim 13 wherein R⁸ is hydrogen or —CH₃; and R⁹ is —CH₂—CH₂—CH(CH₃)₂,


30. A compound according to claim 13 wherein R⁹ represents hydrogen and R⁸ represents


31. A compound according to claim 13 wherein W is CH; X is CH;


38. A compound according to claim 13 wherein W is CH; X is CH; Y is


39. A compound according to claim 13 wherein W is CH; X is C—CH₃ or C—CH₂CH₃; Y is C—CH₃ or C—CH₂CH₃, C—Cl or C—F; and Z is CH.
 40. A compound according to claim 13 wherein W is CH; X is C—OCH₃; Y is C—CH₃, C—CH₂CH₃, C—Cl, C—F, or C—OCH₃; and Z is CH.
 41. A compound according to claim 13 wherein W is CH; X is C—OCH₂CH₃; Y is C—Cl or C—F; and Z is CH.
 42. A compound according to claim 13 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 43. A compound according to claim 13 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 44. A compound according to claim 2 of the formula (Ixb)

wherein R⁷ is hydrogen or alkyl; R¹⁰ is carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —N(R⁶)C(═O)R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —N(R⁶)SO₂R⁴, —N(R⁶)SO₂NY¹Y², —NY¹Y², —OR⁴, —OCF₂H, —OCF₃, —OC(═O)R⁴, —OC(═O)NY¹Y², —S(O)_(n)R⁴ or —S(O)₂NY¹Y²; and p is zero, or an integer 1; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 45. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents CH; and Z represents CH or C—CH₃.
 46. A compound according to claim 44 wherein W represents CH; X represents CH; Z represents CH; and Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C-heteroaryl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², C—C(═O)OR⁴, C—NHC(═O)R⁴, C—CH(OH)aryl, C—S(O)₂NY¹Y², or C—S(O)_(n)R⁴.
 47. A compound according to claim 44 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and Z represents CH.
 48. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents C—CH₃; and Z represents C—CH₃.
 49. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 50. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 51. A compound according to claim 44 wherein R⁷ represents hydrogen.
 52. A compound according to claim 44 wherein p is zero or one.
 53. A compound according to claim 44 wherein R¹⁰ represents cyano, halo, C₁₋₄alkyl, —OR⁴, or —C(═O)NY¹Y².
 54. A compound according to claim 44 wherein R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂, or —C(═O)—N(CH₃)₂.
 55. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents CH; Z represents CH or C—CH₃; R⁷ represents hydrogen; and R¹⁰ represents cyano, halo, C₁₋₄alkyl, —OR⁴ or —C(═O)NY¹Y².
 56. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents CH; Z represents CH or C—CH₃; R⁷ represents hydrogen; and R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃ or —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 57. A compound according to claim 44 wherein W represents CH; X represents CH; Z represents CH; Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², —C(═O)OR⁴, C—NHC(═O)R⁴, C—S(O)₂NY¹Y², or C—S(O)_(n)R⁴; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, halo, C₁₋₄alkyl, —OR⁴, —C(═O)NY¹Y².
 58. A compound according to claim 44 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, halo, C₁₋₄alkyl, OR⁴, or —C(═O)NY¹Y².
 59. A compound according to claim 44 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen; p is zero or one; R¹⁰ represents cyano, halo, chloro, fluoro, methyl], —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 60. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents C—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, halo, C1-4alkyl, —OR⁴, or —C(═O)NY¹Y².
 61. A compound according to claim 44 wherein W represents CH; X represents CH; Y represents C—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 62. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z represents CH; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, halo, C1-4alkyl, —OR⁴, or —C(═O)NY¹Y².
 63. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z represents CH; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 64. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Z represents CH; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, halo, C1-4alkyl, —OR⁴, or —C(═O)NY¹Y².
 65. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Z represents CH; R⁷ represents hydrogen; p is zero or one; and R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 66. A compound according to claim 44 wherein R⁷ represents hydrogen and p is zero.
 67. A compound according to claim 44 wherein R⁷ represents hydrogen; p is one; and R¹⁰ represents cyano, chloro, fluoro, methyl, —OCH₃, —OCH₂CH₃, —C(═O)—NH₂, —C(═O)—NHCH(CH₃)₂ or —C(═O)—N(CH₃)₂.
 68. A compound according to claim 44 wherein W is CH; X is CH; Y is

and Z is CH.
 69. A compound according to claim 44 wherein W is CH; X is C—CH₃ or C—CH₂CH₃; Y

and Z is CH.
 70. A compound according to claim 44 wherein W is CH; X is C—OCH₃; Y is CR, C—CH₃, C—CH₂CH₃, C—Cl or C—OCH₃; and Z is CH.
 71. A compound according to claim 44 wherein W is CH; X is C—OCH₂CH₃; Y is C—F and Z is CH.
 72. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 73. A compound according to claim 44 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 74. A compound according to claim 44 wherein R⁷ represents hydrogen and p is zero.
 75. A compound according to claim 44 wherein R⁷ represents hydrogen; p is one; and R¹⁰ represents —OCH₃, —OCH₂CH₃ or —C(═O)—NHCH(CH₃)₂ attached to position 5 of the indazolyl ring.
 76. A compound according to claim 44 wherein W is CH; X is C—CH₃ or C—CH₂CH₃; Y is C—CH₃ or C—CH₂CH₃ and Z is CH.
 77. A compound according to claim 2 of the formula (Ixc)

wherein R⁷ is hydrogen or alkyl;

is a C₅₋₈cycloalkyl ring; and R¹² is acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy or an acid bioisostere, cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, —C(═O)NY¹Y², —NY¹—C(═O)alkyl, —NY¹SO₂alkyl, —NY¹Y², —SO₂NY¹Y² or alkyl, alkenyl or alkynyl each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, —C(═O)OR⁶, —C(═O)NY¹Y², NY¹Y² or —OR⁵; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 78. A compound according to claim 77 wherein W represents CH; X represents CH; Y represents CH; and Z represents CH or C—CH₃.
 79. A compound according to claim 77 wherein W represents CH; X represents CH; Z represents CH; and Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo; C-haloalkyl, C-heteroaryl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², C—C(═O)OR⁴, C—NHC(═O)R⁴, C—CH(OH)aryl, C—S(O)₂NY¹Y², or C—S(O)_(n)R⁴.
 80. A compound according to claim 77 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and Z represents CH.
 81. A compound according to claim 77 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and Z represents CH.
 82. A compound according to claim 77 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 83. A compound according to claim 77 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 84. A compound according to claim 77 wherein R⁷ represents hydrogen.
 85. A compound according to claim 77 wherein

represents a cyclopentyl, cyclohexyl or cycloheptyl ring.
 86. A compound according to claim 77 wherein q is zero.
 87. A compound according to claim 77 wherein W represents CH; X represents CH; Y represents CH; Z represents CH or C—CH₃; R⁷ represents hydrogen; and

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero.
 88. A compound according to claim 77 wherein W represents CH; X represents CH; Z represents CH; Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C-heteroaryl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², —C(═O)OR⁴, C—NHC(═O)R⁴, C—CH(OH)aryl, C—S(O)₂NY¹Y², C—S(O)_(n)R⁴, R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero.
 89. A compound according to claim 77 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero.
 90. A compound according to claim 77 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z represents CH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero.
 91. A compound according to claim 77 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Z represents CH; R⁷ represents hydrogen;

represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero.
 92. A compound according to claim 77 wherein R⁷ represents hydrogen and q is zero.
 93. A compound according to claim 77 wherein W is CH; X is C—CH₃; Y is C—CH₃; and Z is CH.
 94. A compound according to claim 2 of the formula (Ixd)

wherein X¹ is O, S, SO₂, or NY⁵, where Y⁵ is hydrogen, R⁴, —C(═O)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴ or Y⁵ is —SO₂R⁴; r is zero or an integer one or two; R⁷ is hydrogen or alkyl; and R¹³ is alkyl or, when two R¹³ groups are attached to the same carbon atom, they form an oxo group; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 95. A compound according to claim 94 wherein W represents CH; X represents CH; Y represents CH; and Z represents CH or C—CH₃.
 96. A compound according to claim 94 wherein W represents CH; X represents CH; Z represents CH; and Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C-heteroaryl, C—OR⁴, C—C(═O)R⁴, C—C═O)NY¹Y², C—C(═O)OR⁴, C—NHC(═O)R⁴, C—CH(OH)aryl, C—S(O)₂NY¹Y² or C—S(O)_(n)R⁴.
 97. A compound according to claim 94 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and Z represents CH.
 98. A compound according to claim 94 wherein W represents CH; X represents CH; Y represents C—CH₃; and Z represents C—CH₃.
 99. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 100. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 101. A compound according to claim 94 wherein R⁷ represents hydrogen.
 102. A compound according to claim 94 wherein X¹O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴, or N—SO₂R⁴; and r is zero.
 103. A compound according to claim 94 wherein X¹ is

and r is zero.
 104. A compound according to claim 94 wherein r is zero.
 105. A compound according to claim 94 wherein W represents CH; X represents CH; Y represents CH; Z represents CH or C—CH₃; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴, or N—SO₂R⁴; and r is zero.
 106. A compound according to claim 94 wherein W represents CH; X represents CH; Z represents CH; Y represents C—C₁₋₄alkyl, C-aryl, C—CN, C—NO₂, C-halo, C-haloalkyl, C-heteroaryl, C—OR, C—C(═O)R⁴, C—C═O)NY¹Y², —C(═O)OR⁴, C—NHC(═O)R⁴, C—S(O)₂NY¹Y², C—S(O)_(n)R⁴; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴, or N—SO₂R⁴; and r is zero.
 107. A compound according to claim 94 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

Z represents CH; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴ or N—SO₂R⁴; and r is zero.
 108. A compound according to claim 94 wherein W represents CH; X represents C—CH₃, C—CH₂CH₃, C—CH(CH₃)₂, C—OCH₃, C—OCH₂CH₃, C—Br or C—Cl; Y represents

and r is zero.
 109. A compound according to claim 94 wherein W represents CH; X represents CH; Y represents C—CH₃; Z represents C—CH₃; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴ or N—SO₂R⁴; and r is zero.
 110. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; Z represents CH; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴ or N—SO₂R⁴; and r is zero.
 111. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; Z represents CH; R⁷ represents hydrogen; X¹ is O, N—C(═O)R⁴, N—C(═O)NY¹Y², N—C(═O)OR⁴ or N—SO₂R⁴; and r is zero.
 112. A compound according to claim 94 wherein X¹ is

and r is zero.
 113. A compound according to claim 94 wherein W is CH; X is CH; Y is

and Z is CH.
 114. A compound according to claim 94 wherein W is CH; X is

and Z is CH.
 115. A compound according to claim 94 wherein W is CH; X is C—OCH₃; Y is CH, C—CH₃, C—CH₂CH₃, C—Cl or C—OCH₃; and Z is CH.
 116. A compound according to claim 94 wherein W is CH; X is C—OCH₂CH₃; Y is C—F; and Z is CH.
 117. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—CH₂—CH₂—; and Z represents CH.
 118. A compound according to claim 94 wherein W represents CH; X represents CR² and Y represents CR³ where R² and R³ form the group —CH₂—O—CH₂—; and Z represents CH.
 119. A compound according to claim 94 wherein X¹ is

and r is zero.
 120. A compound according to claim 94 wherein W represents CH; X represents C—CH₃; Y represents C—CH₃ or C—Cl; and Z represents CH.
 121. A compound according to claim 2 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole; 2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 5,6-dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 5-fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-5-methyl-2-(5-morpholin-4-yl-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole hydrochloride; 5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-(4-methoxy-benzylsulfanyl)-4-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole; 2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 2-(4-amino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester; 3-(1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone; 2-(1H-indazol-3-yl)-3H-benzoimidazol-4-ol; 2-phenyl-1H-imidazol[4,5-b]pyrazine; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine; 2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine; 2-(1H-pyrazol-3-yl)-1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole; 5,6-dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole; 3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(2-methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(4-chloro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(4-methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile; 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-pyrazole-4-carboxylic acid ethyl ester; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylic acid ethyl ester; 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 2-(5-methyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-methylsulfanyl-isoxazol-3-yl)-1H-benzoimidazole; 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dichloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; (benzoimidazol-2-yl)-5-methylthio-3-pyrazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole; 2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 2-(5-ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole; 4-chloro-3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazol-5-ol; 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide; 3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, methylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, dimethylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, isopropylamide; 1H-benzoimidazol-5-yl]-carboxylic acid, benzylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethylethyl)-amide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide; 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid; 3-(5,6-dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-pyrazole-4-carboxylic acid; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide; cyclopropanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; methoxyacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopentanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; trimethylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; tert-butylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; butanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; isoxazole-5-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; S(+)-2-methylbutanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; furan-3-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]4-methyl-benzamide; 5,6-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 5-ethyl-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 5-fluoro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(4-nitro-1H-pyrazol-3-yl)-5-trifluoromethoxy-1H-benzoimidazole; 2-(4-nitro-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole; 5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; 5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 5-ethoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide; 2-dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide; 2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea; 1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; -3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-ylamine; 4-methylpiperazine-1-carboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; 1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide; morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; 3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea; 5-methoxy-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide; 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; piperidine-1-carboxylic acid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; morpholine-4-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; piperidine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [2-(2H-tetrazol-5-yl)-ethyl]-amide; 1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 4-methyl-piperazine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl-1H-pyrazol-4-ylamine; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid amide dihydrochloride; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid; 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; 3-(5-nitro-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide; N-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide; N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide; 2-(1H-indazol-3-yl)-3H-benzoimidazol-5-amine; or piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; or or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 122. A compound according to claim 13 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole; 2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 5,6-dimethyl-2-[5-(pyridin-3-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 5-fluoro-2-[5-methylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 5,6-dimethyl-2-(5-phenethylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 4-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dimethyl-2-(5-benzylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 5,6-dimethyl-2-[5-(thiophen-2-ylmethylsulfanyl)-1H-pyrazol-3-yl]-1H-benzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole hydrochloride; 5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 2-(5-(4-methoxy-benzylsulfanyl)₄-propyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-benzylsulfanyl-4-isopropyl-1H-pyrazol-3-yl)₅-methyl-1H-benzoimidazole; 2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-1H-benzoimidazole; 2-(5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 3-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine; 5,6-dimethyl-2-(4-phenyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 2-(5-ethoxy-1H-pyrazol-3-yl)-1H-benzoimidazole; (benzoimidazol-2-yl)-5-methylthio-3-pyrazole; 2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 2-(5-ethyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethylethyl)-amide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzylamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide; cyclopropanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; methoxyacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopentanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; trimethylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; tert-butylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; butanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; isoxazole-5-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; S(+)-2-methylbutanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; furan-3-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide; 2-dimethylamino-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide; 2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl) I H-pyrazol-4-yl]-3-methyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea; 1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; 4-methylpiperazine-1-carboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; 1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide; morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; 3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide; 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; piperidine-1-carboxylic acid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; morpholine-4-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; piperidine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 4-methyl-piperazine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; N-[2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(N′-methylpiperazino)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(isobutyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate; 5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole; 2-(1H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid; 2-(5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole; 5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole; 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)₄-hydroxy-1H-benzimidazole 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole; or or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 123. A compound according to claim 13 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide, Example 3; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole; 6-chloro-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 6-chloro-2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5-methyl-1H-benzoimidazole; 2-(5-methylsulfanyl-1H-pyrazol-3-yl)-5-trifluoromethyl-1H-benzoimidazole; 2-(5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 2-(5-ethylsulfanyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 2-(5-isopropyl-1H-pyrazol-3-yl)-5,6-dimethyl-1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-y)-1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide, (compound denoted as A17-B106); 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzylamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-phenyl-acetamide; cyclopropanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; methoxyacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopentanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; trimethylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; tert-butylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; butanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; isoxazole-5-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; S(+)-2-methylbutanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; furan-3-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-4-methyl-benzamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide; 2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea; 1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; 4-methylpiperazine-1-carboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; 1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide; morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; 3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylmethyl]-amide; 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea, Example 257(h); piperidine-1-carboxylic acid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; morpholine-4-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; piperidine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 4-methyl-piperazine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide; 2-(H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; or N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide, or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 124. A compound according to claim 13 which is 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-methoxy-ethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid propylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(6-ethyl-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid cyclopropylamide; 2-(4-isopropylcarbamoyl-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isobutyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butylamide; 2-(4-isobutyrylamino-1H-pyrazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzylamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-butyramide; cyclopropanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; methoxyacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopentanecarboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; trimethylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; tert-butylacetic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; butanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; isoxazole-5-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; S(+)-2-methylbutanoic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethylurea; cyclopropanecarboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-ethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isobutyramide; cyclopropanecarboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3,5-dimethyl-isoxazole-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; furan-3-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-morpholin-4-yl-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide; N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide; 2-cyclopropyl-N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-acetamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-urea; 1-benzyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; 4-methylpiperazine-1-carboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; 1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea; cyclopropanecarboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; tetrahydropyran-4-carboxylic acid [3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazole-4-yl]amide; morpholine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; 3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea; 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; piperidine-1-carboxylic acid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; morpholine-4-carboxylic acid[3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; piperidine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 3-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; morpholine-4-carboxylic acid [3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; morpholine-4-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-[3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; morpholine-4-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-methyl-3-[3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-ethyl-urea; 4-methyl-piperazine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isobutyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; or 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 125. A compound according to claim 13 which is 3-(5-methoxy-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isopropylamide; 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazole-4-carboxylic acid cyclopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (tetrahydro-pyran-4-yl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid isobutyl-amide; cyclopropanecarboxylic acid[3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]amide; 1,1-dimethyl-3-[3-(1,5,6,7-tetrahydro-s-indacen-2-yl)-1H-pyrazol-4-yl]urea; piperidine-4-carboxylic acid[3-(6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]amide; 3-[6-ethoxy-5-fluoro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea; 3-[3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; piperidine-1-carboxylic acid [3-(5-difluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; cyclopropanecarboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1H-pyrazol-4-yl]amide; piperidine-1-carboxylic acid [3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; piperidine-1-carboxylic acid [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-cyclopropyl-3-[3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; piperidine-1-carboxylic acid [3-(5-fluoro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide; 1-tert-butyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 1-cyclopropyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea; 1-cyclopropylmethyl-3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea; or 3-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 126. A compound according to claim 44 which is 3-(1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanone; 2-(1H-indazol-3-yl)-3H-benzoimidazol-4-ol; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine; 2-(1H-indazole-3-yl)-3H-imidazo[4,5-b]pyridine; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole; 3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole; 3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(5,6-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(2-methoxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(4-chloro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(4-methyl)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile; 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole; 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide; 3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, methylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, dimethylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, isopropylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid; or or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 127. A compound according to claim 44 which is 3-(1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-methoxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methyl-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-6-methoxy-1H-indazole; 3-(5-ethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-isopropyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-bromo-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(3-cyano)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-pyrid-3-yl)-1H-benzoimidazol-2-yl)-1H-indazole; 3-(6-methyl-5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-phenyl-1H-benzoimidazol-2-yl)-1H-indazole, (compound denoted as A60-B63), Example 235(q); 3-(5-(2-fluoro)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-(3,4-methylenedioxy)phenyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5-benzyloxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-methylenedioxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonitrile; 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-ethoxy-1H-indazole; 3-[5-(2-morpholin-4-yl-ethoxy-1H-benzoimidazol-2-yl]-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4-fluoro-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-chloro-1H-indazole; 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-sulfonic acid benzylamide; 3-(5-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-indazole; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-phenyl-methanol; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, ethylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, methylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, isopropylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid, benzamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide; [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid amide dihydrochloride; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 128. A compound according to claim 44 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole; 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole; or 3-(5,6-diethyl-1H-benzoimidazol-2-yl)-1H-indazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid dimethylamide; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 129. A compound according to claim 77 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole; 5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole; or or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 130. A compound according to claim 77 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole; or 5,6-dimethyl-2-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-1H-benzoimidazole; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 131. A compound according to claim 94 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid dimethylamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3-methyl-butan-1-one; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-5-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; or 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrano[4,3-c]pyrazole; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 132. A compound according to claim 94 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; isopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-morpholin-4-yl-methanone; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-[5-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-yl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid dimethylamide; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methyl-propan-1-one; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester; 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-3-methyl-butan-1-one; or 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2,2-dimethyl-propan-1-one; or or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 133. A compound according to claim 94 which is 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; cyclopropyl-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-methanone; 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; prepared 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-pyrrolidin-1-yl-methanone; [3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-piperidin-1-yl-methanone; 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide; or 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid dimethylamide; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 134. A compound according to claim 2 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(N′-methylpiperazino)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(isobutyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate; 5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole; 5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole; 2-(1H-indazol-3-yl)-3H-benzimidazole-4-carboxylic acid; 5-bromo 2-(1H-indazol-3-yl)-3H-benzimidazole; 2-(5-ethoxy-2H-pyrazol-3-yl)-1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2-(5-methyl-2H-pyrazol-3-yl)-1H-benzimidazole; 5,6-dimethyl-2-(5-thiophen-2-yl-2H-pyrazol-3-yl)-1H-benzimidazole; 2-(4-bromo-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-5-methoxy-1H-benzimidazole; 2-(5-ethyl-2H-pyrazol-3-yl)-4-hydroxy-1H-benzimidazole 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (naphthalen-1-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-dimethylamino-benzylamide; 4-({[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-pyrazol-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-isopropyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(3-acetylamino-phenoxy)-propyl]-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid ([2,2′]bithiophenyl-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-cyano-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (5-chloro-benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-benzoimidazol-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-chloro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-sulfamoyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (3-ethoxy-propyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-bromo-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (naphthalen-1-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-dimethylamino-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-nitro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-bromo-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-phenoxy-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-trifluoromethoxy-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-nitro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-chloro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenethyl-amide; 3-(6-phenyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(2,4-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-naphthalen-1-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3,5-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-thianthren-1-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-biphenyl-4-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-p-tolyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-m-tolyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-o-tolyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3,5-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3,4-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-benzo[1,3]dioxol-5-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(4-tert-butyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-hex-1-enyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3,4-dimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol; 4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol; 3-[6-(3,4-dichloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 1-{4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-ethanone; 3-(6-benzo[b]thiophen-2-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3,4,5-trimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 1-{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}-ethanone; 1-{3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-ethanone; 3-[6-(4-benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(2-fluoro-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-benzo[b]thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole; {3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol; 3-[6-(4-ethylsulfanyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(2,4-difluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-trifluoromethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-fluoro-2-methyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-{6-[2-(4-fluoro-phenyl)-vinyl]-1H-benzoimidazol-2-yl}-2H-indazole; 3-{6-[2-(4-chloro-phenyl)-vinyl]-1H-benzoimidazol-2-yl}-2H-indazole; 3-{4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-propionic acid; {4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol; 3-(6-furan-2-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3-benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-isopropyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-methanesulfonyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-acetylamino-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid isopropylamide; [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-methanone; [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzyl-methyl-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,4-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (4′-chloro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3′,5′-dichloro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (4′-fluoro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2′-chloro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 4-[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 2-[5-(benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-phenyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(2-methyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3,7-dimethyl-octa-2,6-dienyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-bromo-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 3-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxymethyl]-benzonitrile; 2-[5-(4-trifluoromethyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-pentafluorophenylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(4-tert-butyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(2-benzenesulfonylmethyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 4-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxymethyl]-benzonitrile; 2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2,3-dichloro-benzenesulfonic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester, 2-[5-(2-morpholin-4-yl-ethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(2-piperidin-1-yl-ethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-methoxy-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-p-tolyl-ethanone; 1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-3,3,4,4,4-pentafluoro-butan-2-one; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-biphenyl-4-yl-ethanone; 1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-butan-2-one; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-dimethylamino-phenyl)-ethanone; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(3-phenyl-isoxazol-5-yl)-ethanone; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-N-phenyl-acetamide; 1-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-3,3-dimethyl-butan-2-one; 1-adamantan-1-yl-2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-ethanone; 2-[5-(1H-benzoimidazol-2-yl]-1H-pyrazol-3-yloxy]-1-naphthalen-2-yl-ethanone; 4-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-benzonitrile; 6-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-3,4-dihydro-1H-quinolin-2-one; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-trifluoromethoxy-phenyl)-ethanone; 5-{2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-acetyl}-2-chloro-benzenesulfonamide; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-(4-methoxy-phenyl)-ethanone; 2-[5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yloxy]-1-cyclopropyl-ethanone; isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 2,2-dimethyl-propionic acid 5-(1H-benzoimidazol-2-yl}-1H-pyrazol-3-yl ester; benzyloxy-acetic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester, benzoic acid 5-(1H-benzoimidazol-2-yl-1H-pyrazol-3-yl ester; 4-methoxy-benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester, phenyl-acetic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 2,3,4,5,6-Pentafluoro-benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; cyclopropanecarboxylic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 2,2,3,3,4,4,4-heptafluoro-butyric acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester, cyclopentanecarboxylic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 3-phenyl-propionic acid 5-(1H-benzoimidazol-2-yl 1H-pyrazol-3-yl ester, biphenyl-4-carboxylic acid 5 (1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 3,5-bis-trifluoromethyl-benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 4-trifluoromethyl-benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; thiophene-2-carboxylic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 135. A compound according to claim 13 which is 2-(5-ethyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; or -2-(5-methyl-2H-pyrazol-3-yl)-5,6-dimethyl-1H-benzimidazole; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 136. A compound according to claim 44 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid benzylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-methylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-ethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-isopropylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-phenethylamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-morpholinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(N′-methylpiperazino)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(isobutyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (naphthalen-1-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-dimethylamino-benzylamide; 4-({[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-trifluoromethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-trifluoromethoxy-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-pyrazol-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-isopropyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(3-acetylamino-phenoxy)-propyl]-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid ([2,2′]bithiophenyl-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-cyano-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-benzoimidazol-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-chloro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 4-sulfamoyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid (furan-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-nitro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid phenylamide; 3-[6-(4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-chloro-4-fluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-m-tolyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-o-tolyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-thiophen-3-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3-chloro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3-methoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(3,5-dimethyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-(6-benzo[1,3]dioxol-5-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-(6-hex-1-enyl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(3,4-dimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol; 4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenol; 3-[6-(3,4,5-trimethoxy-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 1-{5-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-thiophen-2-yl}-ethanone; {3-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol; 3-[6-(2,4-difluoro-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 3-[6-(4-fluoro-2-methyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; {4-[2-(2H-indazol-3-yl)-3H-benzoimidazol-5-yl]-phenyl}-methanol; 3-(6-furan-2-yl-1H-benzoimidazol-2-yl)-2H-indazole; 3-[6-(4-isopropyl-phenyl)-1H-benzoimidazol-2-yl]-2H-indazole; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-acetylamino-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid methylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid isopropylamide; [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-methanone; [2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid benzyl-methyl-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,4-difluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2′-chloro-biphenyl-4-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 4-[2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 2-[5-(benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-phenyl-allyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3,7-dimethyl-octa-2,6-dienyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-bromo-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3,4-dichloro-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(2-benzenesulfonylmethyl-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(biphenyl-4-ylmethoxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; 2-[5-(3-methoxy-benzyloxy)-2H-pyrazol-3-yl]-1H-benzoimidazole; isonicotinic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; benzoic acid 5-(1H-benzoimidazol-2-yl)-1H-pyrazol-3-yl ester; 3-phenyl-propionic acid 5-(1H-benzoimidazol-2-yl 1H-pyrazol-3-yl ester, methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate; 5-methoxy-2-(1H-indazol-3-yl)-1H-benzimidazole; or 5-bromo 2-(1H-indazol-3-yl)-3H-benzimidazole; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 137. A compound according to claim 44 which is 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(cyclohexylmethyl)amide; 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-(2-furfuryl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (benzo[b]thiophen-3-ylmethyl)-amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 3-chloro-benzylamide; 2-(1H-indazol-3-yl)-3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl)amide; 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl)amide; or 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 138. A compound according to claim 2 which is 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide; 2-(1H-Indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide; N-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-isobutyramide; or N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-piperidin-1-yl-acetamide; or an N-oxide, prodrug, acid bioisostere, pharmaceutically acceptable salt or solvate of such compound; or an N-oxide, prodrug, or acid bioisostere of such salt or solvate.
 139. A compound of the of formula (I)

wherein X represents C—R² and W, Y and Z, which may be identical or different, represent CH or CR³; R¹ represents aryl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thieno-pyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl radicals, all these radicals being optionally substituted with one or more radicals X¹, X² or X³ chosen from H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)R⁴, OR⁴, NY¹Y², COR⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)nOR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —OC(—O)R⁴ and optionally substituted thienyl; R² and R³ are such that: either R² and R³, which may be identical or different, represent H, R⁴, halogen, haloalkyl, OH, NO₂, CN, OR⁴, COR⁴, S(O)R, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y² or —OC(═O)R⁴, or R² represents H, R⁴, halogen, haloalkyl, OH, NO₂, CN, O, COR⁴, S(O)_(n)R⁴, —C(═O)NY Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y² or —OC(═O)R⁴ and R³ represents alkyl, haloalkyl, halogen or OR⁶, or R² and R³ together form a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S; R⁴ represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from optionally substituted aryl, halogen, alkyl, hydroxyalkyl, OH, OR⁵, C(═O)NY³Y⁴, NY³Y⁴, alk-NY³Y⁴ and C(═O)OR⁶; R⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl; Y¹ and Y² are such that: either Y¹ and Y² which may be identical or different, represent H or optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y¹ and Y² form, together with the nitrogen atom to which they are attached, a cyclic amino radical; Y³ and Y⁴ are such that: either Y³ and Y⁴, which may be identical or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y³ and Y⁴ form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical; A₅ represents H or alkyl; R⁶ is chosen from the values of R⁵; where all the alkyl, or alk, which represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals furthermore being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—COalk), —C(═O)OR⁶, acyl —C(═O)R⁶, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³Y⁴ and NY³Y⁴ radicals, the latter radicals containing alkyl, aryl and heteroaryl being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH—C(O)R⁵, the phenyl radicals furthermore being optionally substituted with a dioxole radical; n represents an integer from 0 to 2, provided that when R¹ represents an indazolyl radical to give the compounds of formula (F) below:

with X representing H, R² or R³ as defined above, then W of formula (F) necessarily represents H or unsubstituted alkyl; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 140. A compound according to claim 139 of the formula (Ia)

wherein Xa represents C—R²a; Wa, Ya and Za, which may be identical or different, represent CH or CR³a; R₁a represents aryl or heteroaryl chosen from pyrazolyl, triazolyl and indazolyl radicals, all these radicals being optionally substituted with one or more radicals X¹a, X²a or X³a chosen from H, halogen, OH, R⁴a, OR⁴a, NY¹aY²a, S(O)_(n)R⁴a, —C(═O)NY¹aY²a, —C(═O)OR⁴a, —N(R⁶a)C(═O)R⁴a, —N(R⁶a)SO₂R⁴a, —N(R⁶a)C(═O)NY¹aY²a, —N(R⁶a)C(═O)OR⁴a, —OC(═O)NY¹aY²a, —OC(═O)R⁴a, —OS(O)_(n)R⁴a and thienyl optionally substituted with an alkyl radical; R²a and R³a are such that: either R²a and R³a, which may be identical or different, represent H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a or —C(═O)OH, and R³a represents alkyl, halogen or OR⁶a, or R²a represents H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a or —C(═O)OH, and R³a represents alkyl, halogen or OR⁶a, or R²a and R³a together form an —O—CH₂—O— or —O—CH₂—CH₂—O— ring, R⁴a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from optionally substituted aryl, halogen, alkyl, hydroxyalkyl, OH, OR⁵a, C(═O)NY³aY⁴a, NY³aY⁴a, alk-NY³aY⁴a and C(═O)OR⁶a, R⁵a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, all these radicals being optionally substituted; Y¹a and Y²a are such that: either Y¹a and Y²a, which may be identical or different, represent H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, aryl or heteroaryl, all these radicals being optionally substituted, or Y¹a and Y²a form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical; Y³a and Y⁴a are such that: either Y³a and Y⁴a, which may be identical or different, represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y³a and Y⁴a form, together with the nitrogen atom to which they are attached, a cyclic amino radical; A₅ represents H or alkyl; all the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals furthermore being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH—C(O)R⁶a), —C(═O)OR⁶a, acyl —C(═O)R⁶a, hydroxyalkyl, carboxyalkyl, S(O)_(n)-alk, S(O), —NH₂, S(O), —NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, —C(═O)—NY³aY⁴a and NY³aY⁴a radicals, the latter radicals containing alkyl, aryl and heteroaryl themselves being optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, alkoxy radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH—C(O)R⁶a, the phenyl radicals furthermore being optionally substituted with a dioxole radical; R⁶a is chosen from the values of R⁵a, n represents an integer from 0 to 2; or or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 141. A compound of formula (I)

wherein X represents C—R²; and W, Y and Z, which may be identical or different, represent CH or CR³; R¹ represents aryl or heteroaryl chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thieno-pyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyrano-pyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydro-pyridinopyrazolyl radicals, all these radicals optionally being substituted with one or more radicals X¹, X² or X³ chosen from H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)R⁴, OR⁴, NY¹Y², COR⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴⁰, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴, S(O)NY¹Y², —OC(═O)NY¹Y², —OS(O)_(n)R^(, —OC(═O)R) ⁴ and optionally substituted thienyl, R² and R³ are such that: either R² and R³, which may be identical or different, represent H, R⁴, halogen, haloalkyl, OH, NO², CN, OR⁴, COR⁴, S(O)_(n)R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R6)SO2R4, —N(R6)C(═O)NY1Y2, —N(R6)C(═O)OR4, —S(O)_(n)OR4, —S(O)_(n)NY1Y2, —OC(═O)NY¹Y² or —OC(═O)R⁴ or R² represents H, R⁴, halogen, haloalkyl, OH, NO₂, CN, OR⁴, COR⁴, S(O)_(n)—R⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —NY¹Y², —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y² or —OC(═O)R⁴ and R³ represents alkyl, haloalkyl, halogen and OR⁶ or R² and R³ together form a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S; R⁴ represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, hetero-arylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl, OH, OR⁵, C(═O)NY³Y4, NY³Y⁴ and C(═O)OR⁶; R⁵ represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl; R⁶ represents H and C₁-C₄ alkyl; n represents an integer from 0 to 2 Y¹ and Y² are such that: either Y¹ and Y², which may be identical or different, represent H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, all these radicals being optionally substituted with one or more radicals chosen from hydroxyl, —C(═O)—NY³Y⁴, —C(═O)OR⁶ and NY³Y⁴, or Y¹ and Y² form, together with the nitrogen atom to which they are attached, a cyclic amino radical; Y³ and Y⁴ are such that: either Y³ and Y⁴, which may be identical or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y³ and Y⁴ form, together with the nitrogen atom to which they are attached, a cyclic amino radical; A₅ represents H or alkyl; provided that when R¹ represents an indazolyl radical to give the compound of formula (F) below:

with X representing H, R² or R³ as defined above, then W of formula F necessarily represents H or unsubstituted alkyl; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 142. A compound according to claim 139 of the formula (Ia)

wherein Xa represents C—R²a; and Wa, Ya and Za, which may be identical or different, represent CH or CR³a; R¹a represents aryl or heteroaryl chosen from pyrazolyl, triazolyl and indazolyl radicals, all these radicals being optionally substituted with one or more radicals X¹a, X²a or X³a chosen from H, halogen, OH, R⁴a, OR⁴a, NY¹aY²a, S(O)_(n)R⁴a, —C(═O)NY¹aY²a, —C(═O)OR⁴a, —N(R⁶a)C(═O)R⁴a, —N(R⁶a)SO₂R⁴a, —N(R⁶a)C(═O)NY¹aY²a, —N(R⁶a)C(═O)OR⁴a, —OC(═O)NY¹aY²a and —OC(═O)R⁴a, —OS(O)_(n)R⁴a and thienyl optionally substituted with an alkyl radical, R²a and R³a are such that: either R²a and R³a, which may be identical or different, represent H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a, or —C(═O)OH, and R³a represents alkyl, halogen or OR⁶a, or R²a represents H, R⁴a, halogen, OH, OR⁴a, C(═O)NY¹aY²a, —C(═O)OR⁴a, or —C(═O)OH, and R³a represents alkyl, halogen or OR⁶, or R²a and R³a together form an —O—CH₂—O or —O—CH₂—CH₂—O— ring; R⁴a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these radicals being optionally substituted with one or more radicals chosen from aryl, OH, OR⁵a, C(═O)NY³aY⁴a, NY³aY⁴a and C(═O)OR⁶a; R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl; R⁶a represents H and C₁-C₄ alkyl; n represents an integer from 0 to 2; Y¹a and Y²a are such that: either Y¹a and Y²a, which may be identical or different, represent H, alkyl, cycloalkyl, aryl or heteroaryl, all these radicals being optionally substituted with one or more radicals chosen from hydroxyl, —C(═O)—NY³Y⁴, —C(═O)OR¹ and NY³Y⁴, or Y¹a and Y²a form, together with the nitrogen atom to which they are attached, a cyclic amino radical; Y³a and Y⁴a are such that: either Y³a and Y⁴a, which may be identical or different, represent hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y³a and Y⁴a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, A₅ represents H or alkyl; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 143. A compound according to claim 139 of the formula IA

wherein A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a bicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N and S, this heterocycle A being optionally substituted with one or more radicals XA¹, XA² or XA³ chosen from H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)R⁴, OR⁴, NY¹Y², COR⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —OC(═O)R⁴ and optionally substituted thienyl; A₁, A₂, A₃ and A₄, which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical, NA⁶A⁷ such that either A⁶ and A⁷, which may be identical or different, are chosen from a hydrogen atom and optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl radicals, or A⁶ and A⁷ form, together with the nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among A₁, A₂, A₃ and A₄ can form, with the benzimidazole radical to which they are attached, a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S; A₅ represents a hydrogen atom or an alkyl radical; R⁶b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, all the alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl radicals present in the above radicals being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶), —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)—N(alk)₂ radicals, all the above alkyl, alkenyl, alkoxy and alkylthio radicals being linear or branched and containing not more than 4 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical; n represents an integer from 0 to 2; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 144. A compound according to claim 139 of the formula (IAa):

in which Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA¹, XA² or XA³ chosen from H, halogen, haloalkyl, OH, R⁴, NO₂, CN, S(O)_(n)—R⁴, OR⁴, NY¹Y², COR⁴, —C(═O)NY¹Y², —C(═O)OR⁴, —C(═O)OH, —N(R⁶)C(═O)R⁴, —N(R⁶)SO₂R⁴, —N(R⁶)C(═O)NY¹Y², —N(R⁶)C(═O)OR⁴, —S(O)_(n)OR⁴, —S(O)_(n)NY¹Y², —OC(═O)NY¹Y², —OS(O)_(n)R⁴, —OC(═O)R⁴ and optionally substituted thienyl; A₁a, A₂a, A₃a and A₄a, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶aA⁷a such that either A⁶a and A⁷a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals from among A₁a, A₂a, A₃a and A₄a may form, with the benzimidazole radical to which they are attached, an optionally substituted 5- to 6-membered carbon-based ring containing one or two oxygen atoms, A₅a represents a hydrogen atom or an alkyl radical, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals; all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 145. A compound according to claim 139 of the formula IA

wherein A represents a saturated heterocyclic radical which is either a 5- or 6-membered monocyclic radical or a bicyclic radical that is not more than 10-membered, these members being such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbon member or a hetero atom member chosen from O, N and S, this heterocycle A optionally being substituted with one or more radicals XA¹, XA² or XA³ chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals or thienyl radicals optionally substituted with an alkyl radical; A₁, A₂, A₃ and A₄, which may be identical or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶A⁷ such that either A⁶ and A⁷, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl radicals, or A⁶ and A⁷ form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical, it being understood that two consecutive radicals among A₁, A₂, A₃ and A₄ can form, with the benzimidazole radical to which they are attached, a 5- to 6-membered carbon-based ring containing one or more hetero atoms, which may be identical or different, chosen from O, N and S; A₅ represents a hydrogen atom or an alkyl radical; all the phenyl, phenoxy, cycloalkyl and heteroarylalkyl radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals; all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 146. A compound according to claim 139 of formula IAb

wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals chosen from halogen atoms and OH, alkyl, alkynyl, —OR⁶b including alkoxy, —COR⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b, phenyl, phenylalkyl, CF₃, OCF₃, NO₂, CN, NY¹bY²b, —NH—C(═O)NY¹bY²b, acylamino (NH—CO—R⁶b), S(O)_(n)-alk, S(O)_(n)—NY¹ bY²b, —C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)R⁶b, —NH—S(O)_(n)R⁶b, —NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b, —OC(═O)NY¹bY²b and thienyl radicals, all these radicals being optionally substituted, with NY¹bY²b such that either Y¹b and Y²b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical; A₁b, A₂b, A₃b and A₄b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, —OR⁶b including alkoxy, —CO—R⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benz-imidazolylalkyl radicals, all these radicals being optionally substituted, or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted, it being understood that two consecutive radicals among A₁b, A₂b, A₃b and A₄b can form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimid-azole radical or an optionally substituted 4,5-methylenedioxybenzimidazole radical; A₅b represents a hydrogen atom; all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b), —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)—N(alk)₂ radicals, with n representing an integer from 0 to 2, and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamantyl, quinoline, quinolone, dihydroquinolone, —NH-phenyl, phenylalkyl or cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF₃, OCF₃, alkyl, phenyl-S(O)_(n)-alk-phenyl, alkoxy, NH₂, NHalk, N(alk)₂, SO₂NH₂, SO₂Nalk or SO₂N(alk)₂ radical, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 147. A compound according to claim 139 of the formula IAb

wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals chosen from halogen atoms and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF₃, OCF₃, NO₂, CN, NY¹bY²b, —NH—C(═O)NY¹bY²b, acylamino (NH—CO—R⁶b), S(O)_(n)-alk, S(O), —NY¹bY²b, —C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)Rb, —NH—S(O)_(n)R⁶b, —NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b, —OC(═O)NY¹bY²b and thienyl radicals which are optionally substituted, with NY¹bY²b such that either Y¹b and Y²b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical; A₁b, A₂b, A₃b and A₄b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl radicals, all these radicals being optionally substituted, or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted, it being understood that two consecutive radicals among A₁b, A₂b, A₃b and A₄b can form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or an optionally substituted 4,5-methylenedioxybenzimidazole radical; A₅b represents a hydrogen atom; all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b), —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O)_(n)—NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) or C(═O)—N(alk)₂ radicals; with n representing an integer from 0 to 2, and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl or cycloalkylalkyl, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 148. A compound according to claim 139 of the formula IAb

wherein Ab represents a pyrazolyl radical substituted with one or two radicals such that one is chosen from hydrogen, halogen atoms and alkyl, alkynyl, —COR⁶b, phenyl, phenylalkyl, CF₃, NO₂, CN, NY¹bY²b, —NH—C(═O)NY¹bY²b, NH—CO—R⁶b, S(O)_(n)-alk, S(O)_(n)—NY¹bY²b, —C(═O)—NY¹bY²b, —C(═O)OR⁶b, —NH—C(═O)R⁶b, —NH—S(O)_(n)R⁶b, —NH—C(═O)OR⁶b, —N(R⁶b)C(═O)NY¹bY²b and thienyl radicals, all these radicals being optionally substituted, and the other is chosen from OH, —OR⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b, —O(CH₂), —CO—R⁶b and —OC(═O)NY¹bY²b radicals, all these radicals being optionally substituted, with NY¹bY²b such that Y¹b and Y²b, which may be identical or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y¹b and Y²b form, together with the nitrogen atom to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl radical; A₁b, A₂b, A₃b and A₄b, which may be identical or different, are such that two of them represent hydrogen and the other two, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, —OR⁶b (including alkoxy), —CO—R⁶b, —O—COR⁶b, —OS(O)_(n)R⁶b, —O(CH₂)_(n)—CO—R⁶b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benz-imidazolylalkyl radicals, all these radicals being optionally substituted, or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical itself optionally substituted; A₅b represents a hydrogen atom, all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH—COR⁶b), —C(═O)OR⁶b, acyl —C(═O)R⁶b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S(O)_(n)-alk, S(O)_(n)—NH₂, S(O), —NH(alk), S(O)_(n)—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk) and C(═O)N(alk)₂ radicals; with n representing an integer from 0 to 2; and R⁶b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamantyl, quinoline, quinolone, dihydroquinolone, —NH-phenyl, phenylalkyl and cycloalkylalkyl, all these radicals being optionally substituted with a morpholino, piperidyl or phenyl radical itself optionally substituted with one or more radicals chosen from halogen atoms and the cyano, CF₃, OCF₃, alkyl, phenyl-S(O)_(n)-alk-phenyl, alkoxy, NH₂, NHalk, N(alk)₂, SO₂NH₂, SO₂Nalk or SO₂N(alk)₂ radical, all the alkyl, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 10 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 149. A compound according to claim 139 of the formula IAb

wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals; A₁b, A₂b, A₃b and A₄b, which may be identical or different, are chosen from a hydrogen atom; halogen atom; hydroxyl, alkyl, alkenyl optionally substituted with phenyl itself optionally substituted with one or more halogen atoms, alkoxy, nitro, cyano, furyl, thienyl optionally substituted with acyl COalk, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy which are optionally substituted; and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or different, are chosen from hydrogen, alkyl, alkoxyalkyl containing not more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino NH—C(O)alk, phenyl, optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl optionally substituted with one or more alkyl radicals, naphthylalkyl, thienylalkyl optionally substituted with alkyl or thienyl, piperidylalkyl optionally substituted with a carboxyl radical which is free, salified or esterified with an alkyl radical, pyridylalkyl optionally substituted with one or more radicals chosen from halogen and CF3, benzothienylalkyl, pyrazolylalkyl optionally substituted with one or more alkyl radicals, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl, and benzimidazolylalkyl optionally substituted with one or more alkyl radicals; or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, the piperazinyl radical being optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals among A₁b, A₂b, A₃b and A₄b can form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or an optionally substituted 4,5-methylenedioxybenzimidazole radical; A₅a represents a hydrogen atom; the phenyl, phenoxy and phenylalkyl radicals above being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NH—COalk radicals, a carboxyl radical which is free, salified or esterified with an alkyl radical, and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, SO₂alk, SO₂NH₂, SO₂—NH(alk), SO₂—N(alk)₂, CF₃, OCF₃, NO₂, CN, phenyl, itself optionally substituted with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, —C(═O)—NH₂, —C(═O)—NH(alk), C(═O)—N(alk)₂ and C(O)CH₃ radicals; all the alkyl or alk, alkenyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 4 carbon atoms, all the phenyl radicals of the above radicals furthermore being optionally substituted with a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 150. A compound according to any one of claims 146, 147, 148 or 149 wherein when one of A₁b, A₂b, A₃b and A₄b represents a carboxyl radical amidated with a radical NA⁶bA⁷b, then either one of A⁶b and A⁷b represents a hydrogen atom or an alkyl radical and the other of A⁶b and A⁷b is chosen from the values defined for A⁶b and A⁷b, or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a 5- or 6-membered cyclic radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 151. A compound according to claim 139 wherein X, W, Y and Z are such that two or three of them represent CH and the others are chosen from CR² and CR³ and, when two of them represent CH and CR² and CR³ are adjacent to each other, can form a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 152. A compound according to claim 143 or claim 145 wherein A₁, A₂, A₃ and A₄ are such that two or three of them represent a hydrogen atom and, when two of them represent a hydrogen atom and the other two are on adjacent carbons, can form a dioxole radical; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 153. A compound according to claim 139 of the formula (IAa)

wherein Aa represents a pyrazolyl, triazolyl or indazolyl radical, this heterocycle Aa being optionally substituted with one or more radicals XA¹, XA² or XA³ chosen from halogen atoms, alkyl, alkoxy, alkylthio radicals and thienyl radicals optionally substituted with an alkyl radical, A₁a, A₂a, A₃a and A₄a, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶aA⁷a such that either A⁶a and A⁷a, which may be identical or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A⁶a and A⁷a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals from among A₁a, A₂a, A₃a and A₄a may form, with the benzimidazole radical to which they are attached, an optionally substituted 5- to 6-membered carbon-based ring containing one or two oxygen atoms, A5a represents a hydrogen atom or an alkyl radical, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl, and dioxole radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 6 carbon atoms; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 154. A compound according to claim 139 wherein R¹ represents a pyrazolyl or indazolyl radical.
 155. A compound according to claim 144 or claim 153 wherein Aa represents an optionally substituted pyrazolyl or an optionally substituted indazolyl radical, A₁a, A₂a, A₃a and A₄a are chosen from the following values: A₁a represents hydrogen or carboxyl or forms a ring with the adjacent member A₂a; A₄a represents hydrogen or carboxyl or forms a ring with the adjacent member A₃a; A₂a represents a carboxyl radical that is free, salified, esterified with an optionally substituted alkyl radical or an amidated carboxyl; A₂a and A₃a represent two optionally substituted alkyl radicals; and A₅a represents hydrogen; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 156. A compound according to claim 139 of the formula (IAb):

wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl, alkoxy and thienyl radicals, A₁b, A₂b, A₃b and A₄b, which may be identical or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA⁶bA⁷b such that either A⁶b and A⁷b, which may be identical or different, are chosen from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or A⁶b and A⁷b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals from among A₁b, A₂b, A₃b and A₄b may form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or 4,5-methylenedioxybenzimidazole radical, A₅b represents a hydrogen atom, the phenyl and phenoxy radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and free, salified or esterified carboxyl radicals, all the alkyl, alkoxy and alkylthio radicals above being linear or branched and containing not more than 4 carbon atoms; or the racemic, enantiomeric or diastereoisomeric isomer form of such compound, or the addition salt with a mineral or an organic acid or with a mineral base of such compound.
 157. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 2, together with one or more pharmaceutically acceptable carriers or excipients.
 158. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 159. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of Syk comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 160. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of KDR comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 161. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of KDR comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 162. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of tie2 comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 163. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of tie2 comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 164. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of ITK comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 165. A method of treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the catalytic activity of ITK comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 166. A method of treating inflammatory disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 167. A method of treating inflammatory disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 168. A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 169. A method of treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 170. A method of treating Chronic Obstructive Pulmonary Disease, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 171. A method of treating Chronic Obstructive Pulmonary Disease, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 172. A method of treating asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, systemic lupus erythromatosis, viral infections, bacterial infections, parasitic infections, graft vs. host disease, organ transplant rejection, reperfusion injury, Crohn's disease or ulcerative colitis, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 173. A method of treating asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, systemic lupus erythromatosis, viral infections, bacterial infections, parasitic infections, graft vs. host disease, organ transplant rejection, reperfusion injury, Crohn's disease or ulcerative colitis, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 174. A method of treating cancers, atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis or fibrotic diseases of the viscera, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 175. A method of treating cancers, atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis or fibrotic diseases of the viscera, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 176. A method of treating asthma, atopic dermatitis, psoriasis, dermatitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease, acute and chronic urticaria, allergic rhinitis or allergic conjunctivitis, arthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis, Chronic Obstructive Pulmonary Disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft v host disease and other transplant associated rejection events, reperfusion injury, Crohn's disease, ulcerative colitis, cancers, tumours, atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera, or inflammatory bowel disease, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 177. A method of treating asthma, atopic dermatitis, psoriasis, dermatitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease, acute and chronic urticaria, allergic rhinitis or allergic conjunctivitis, arthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis, Chronic Obstructive Pulmonary Disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, diabetes, multiple sclerosis, restenosis, myocarditis, B cell lymphomas, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft v host disease and other transplant associated rejection events, reperfusion injury, Crohn's disease, ulcerative colitis, cancers, tumours, atherosclerosis, degenerative muscle diseases, obesity, conjestive heart failure, Parkinson's, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera, or inflammatory bowel disease, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 178. A method of inhibiting angiogenesis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 179. A method of inhibiting angiogenesis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 180. A method according to claim 168 wherein the cancer being treated is colorectal, prostate, breast, thyroid, skin, colon or lung cancer.
 181. A method according to claim 169 wherein the cancer being treated is colorectal, prostate, breast, thyroid, skin, colon or lung cancer.
 182. A method of treating asthma in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 183. A method of treating asthma in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 184. A method of treating psoriasis in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 185. A method of treating psoriasis in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 186. A method of treating joint inflammation in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 187. A method of treating joint inflammation in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 188. A method of treating inflammatory bowel disease in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a compound according to claim
 2. 189. A method of treating inflammatory bowel disease in a patient in need thereof comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1 or claim
 157. 190. A process for preparing the compound of formula (I) according to claim 139, characterized in that an acid of formula (D): R1′-COOH  (D) in which R1′ has the meaning given in claim 139 for R¹, in which the possible reactive functions are optionally protected with protecting groups, is subjected to an esterification reaction to give an acid ester of formula (II) R1′-COOalk  (II) in which R1′ has the meaning given above and alk represents an alkyl radical, is subjected to a reduction reaction to give the alcohol of formula (III): R1′-CH2OH  (III) in which R1′ has the meaning given above, which is oxidized to the aldehyde of formula (IV): R1′-CHO  (IV) in which R1′ has the meaning given above, and the compound of formula (D) or compound of formula (IV) as defined above is reacted with a diamine of formula (V):

in which W′, X′, Y′ and Z′ have the meanings given in claim 139, respectively, for W, X, Y and Z, in which the possible reactive functions are optionally protected with protecting groups, to give a compound of formula (I′):

in which A5′ has the meaning given in claim 139 for A₅, in which the possible reactive functions are optionally protected with protecting groups, and R1′, W′, X′, Y′ and Z′ have the meanings given above, the compound of formula (1′) being a compound which may be a compound of formula (I) and which, in order to obtain a compound or other compound of formula (I), may be subjected, if desired and if necessary, to one or more of the following conversion reactions, in any order: a) an esterification reaction of an acid function, b) a saponification reaction of an ester function to an acid function, c) an oxidation reaction of an alkylthio group to the corresponding sulphoxide or sulphone, d) a reaction for conversion of a ketone function to an oxime function, e) a reaction for reduction of the free or esterified carboxyl function to an alcohol function, f) a reaction for conversion of the alkoxy function to a hydroxyl function, or alternatively of the hydroxyl function to an alkoxy function, g) a reaction for oxidation of an alcohol function to an aldehyde, acid or ketone function, h) a reaction for conversion of a nitrile radical to a tetrazolyl, i) a reaction for removal of the protecting groups that may be borne on the protected reactive functions, j) a salification reaction with a mineral or organic acid or with a base to give the corresponding salt, k) a reaction for resolution of the racemic forms into resolved products, the said compound of formula (I) thus being obtained in any possible racemic, enantiomeric or diastereoisomeric isomer form.
 191. A process for preparing the compound of formula (I) according to claim 139, corresponding to formula (IA) according to any one of claims 143 or 145 characterized in that an acid of formula (D): A′-COOH  (D) in which A′ has the meaning given in any one of claims 143 or 145 for A, in which the possible reactive functions are optionally protected with protecting groups, is subjected to an esterification reaction to give an acid ester of formula (II) A′-COOalk  (II) in which A′ has the meaning given above and alk represents an alkyl radical, is subjected to a reduction reaction to give the alcohol of formula (III): A′-CH2OH  (III) in which A′ has the meaning given above, which is oxidized to the aldehyde of formula (IV): A′-CHO  (IV) in which A′ has the meaning given above, and the compound of formula (D) or compound of formula (IV) as defined above are reacted with a diamine of formula (V):

in which A1′, A2′, A3′ and A4′ have the meanings given in any one of claims 143, 145 or 152, respectively, for A₁, A₂, A₃ and A₄, in which the possible reactive functions are optionally protected with protecting groups, to give a compound of formula (IA′):

in which A₅′ has the meaning given in any one of claims 143, 145 or 152 for A₅, in which the possible reactive functions are optionally protected with protecting groups, and A1′, A2′, A3′ and A4′ have the meanings given above, the compound of formula (IA′) is a compound which may be a compound of formula (IA) and which, in order to obtain a compound or another compound of formula (IA), may be subjected, if desired and if necessary, in any order, to one or more of the conversion reactions chosen from among the reactions a) to k) defined in claim 190, the said compound of formula (IA) thus obtained being in any possible racemic, enantiomeric or diastereoisomeric isomer form.
 192. A method according to claim 168 wherein the cancer being treated is breast cancer, stomach cancer, cancer of the ovaries, cancer of the colon, lung cancer, brain cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the genito-urinary tract, bladder, prostate, bone cancer or cancer of the pancreas.
 193. A method according to claim 169 wherein the cancer being treated is breast cancer, stomach cancer, cancer of the ovaries, cancer of the colon, lung cancer, brain cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the genito-urinary tract, bladder, prostate, bone cancer or cancer of the pancreas. 